Oxytocin

Oxytocin
Systematic (IUPAC) name
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
Identifiers
CAS number 50-56-6
ATC code H01BB02
PubChem CID 439302
DrugBank DB00107
ChemSpider 388434
Chemical data
Formula C43H66N12O12S2 
Mol. mass 1007.19 g/mol
Pharmacokinetic data
Bioavailability nil
Protein binding 30%
Metabolism hepatic oxytocinases
Half-life 1–6 min
Excretion Biliary and renal
Therapeutic considerations
Pregnancy cat. A(AU)
Legal status POM (UK) ℞-only (US)
Routes Intranasal, IV, IM
Not to be confused with Oxycodone or OxyContin.

Oxytocin (pronounced /ˌɒksɨˈtoʊsɪn/) is a mammalian hormone that acts primarily as a neurotransmitter in the brain. Also known as alpha-hypophamine (α–hypophamine), oxytocin has the distinction of being the very first polypeptide hormone to be sequenced and synthesized biochemically by Vincent du Vigneaud et al. in 1953.[1]

Oxytocin is best known for its roles in female reproduction: 1) it is released in large amounts after distension of the cervix and vagina during labor, and 2) after stimulation of the nipples, facilitating birth and breastfeeding. Recent studies have begun to investigate oxytocin's role in various behaviors, including orgasm, social recognition, pair bonding, anxiety, and maternal behaviors.[2] For this reason, it is sometimes referred to as the "cuddle hormone." [3]

Contents

Actions

Oxytocin has peripheral (hormonal) actions, and also has actions in the brain. The actions of oxytocin are mediated by specific, high affinity oxytocin receptors. The oxytocin receptor is a G-protein-coupled receptor which requires Mg2+ and cholesterol. It belongs to the rhodopsin-type (class I) group of G-protein-coupled receptors.

Peripheral (hormonal) actions

The peripheral actions of oxytocin mainly reflect secretion from the pituitary gland. (See oxytocin receptor for more detail on its action.)

It is also important to note that more studies have been done to examine sexual arousal in women compared to men. Women experience longer orgasms compared to men and have a more complex reproductive endocrine system with clearly identified cycles such as, menstruation, lactation, menopause, and pregnancy.[12] This allows more opportunities to measure and examine the hormones related to sexual arousal.

Oxytocin evokes feelings of contentment, reductions in anxiety, and feelings of calmness and security around a mate.[13] In order to reach full orgasm, it is necessary that brain regions associated with behavioral control, fear and anxiety are deactivated; which allows individuals to let go of fear and anxiety during sexual arousal. Many studies have already shown a correlation of oxytocin with social bonding, increases in trust, and decreases in fear. One study confirmed that there was a positive correlation between oxytocin plasma levels and an anxiety scale measuring the adult romantic attachment.[14] This suggests that oxytocin may be important for the inhibition of brain regions that are associated with behavioral control, fear, and anxiety, thus allowing orgasm to occur.

Actions within the brain

Oxytocin secreted from the pituitary gland cannot re-enter the brain because of the blood-brain barrier. Instead, 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 which are collaterals from them.[37] 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.

Drug forms

Synthetic oxytocin is sold as proprietary medication under the trade names Pitocin and Syntocinon and also as generic oxytocin. Oxytocin is destroyed in the gastrointestinal tract, and therefore must be administered by injection or as nasal spray. Oxytocin has a half-life of typically about three minutes in the blood. Oxytocin given intravenously does not enter the brain in significant quantities - it is excluded from the brain by the blood-brain barrier. There is no evidence for significant central nervous system entry of oxytocin by nasal spray. Oxytocin nasal sprays have been used to stimulate breastfeeding but the efficacy of this approach is doubtful.[47]

Injected oxytocin analogues are used for labor induction and to support labor in case of non-progression of parturition. It has largely replaced ergometrine as the principal agent to increase uterine tone in acute postpartum haemorrhage. Oxytocin is also used in veterinary medicine to facilitate birth and to increase milk production. 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).

Some have suggested that the trust-inducing property of oxytocin might help those who suffer from social anxieties and mood disorders, while others have noted the potential for abuse with confidence tricks[48][49] and military applications.[50]

Potential adverse reactions

Oxytocin is relatively safe when used at recommended doses. Potential side effects include:

Synthesis, storage, and release

oxytocin, prepro- (neurophysin I)
Identifiers
Symbol OXT
Alt. symbols OT
Entrez 5020
HUGO 8528
OMIM 167050
RefSeq NM_000915
UniProt P01178
Other data
Locus Chr. 20 p13

The oxytocin peptide is synthesized as an inactive precursor protein from the OXT gene.[51][52][53] This precursor protein also includes the oxytocin carrier protein neurophysin I.[54] The inactive precursor protein is progressively hydrolyzed into smaller fragments (one of which is neurophysin I) via a series of enzymes. The last hydrolysis which releases the active oxytocin nonapeptide is catalyzed by peptidylglycine alpha-amidating monooxygenase (PAM).[55]

The activity of the PAM enzyme system is dependent upon ascorbate which is a necessary vitamin cofactor. By chance, it was discovered that sodium ascorbate by itself stimulated the production of oxytocin from ovarian tissue over a range of concentrations in a dose-dependent manner.[56] 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.[57]

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.[37] The peripheral hormonal and behavioral brain effects of oxytocin it has been suggested are coordinated through its common release through these collaterals.[37] Oxytocin is also made by some neurons in the paraventricular nucleus that project to other parts of the brain and to the spinal cord.[58] 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 the corpus luteum,[59][60] the interstitial cells of Leydig,[61] the retina,[62] the adrenal medulla,[63] the placenta,[64] the thymus[65] and the pancreas.[66] 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.

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.

Male

The Leydig cells in some species have also been shown to possess the biosynthetic machinery to manufacture testicular oxytocin de novo, specifically, in rats (who can synthesize Vitamin C endogenously), and in guinea pigs who (like humans) require an exogenous source of vitamin C (ascorbate) in their diets.[67]

Structure and relation to vasopressin

Oxytocin is a peptide of nine amino acids (a nonapeptide). The sequence is cys – tyr – ile – gln – asn – cys – pro – leu – gly - NH2 (CYIQNCPLG-NH2). The cysteine residues form a sulfur bridge. Oxytocin has a molecular mass of 1007 daltons. One international unit (IU) of oxytocin is the equivalent of about 2 micrograms of pure peptide.

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 dithiol nonapeptide called oxytoceine.[68] It has been theorized that open chain oxytoceine (the reduced form of oxytocin) may also act as a free radical scavenger (by donating an electron to a free radical); oxytoceine may then be oxidized back to oxytocin via the redox potential of dehydroascorbate <---> ascorbate.[69]

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

The structure of oxytocin is very similar to that of vasopressin (cysteine – tyrosine – phe – gln – asn – cys – pro – arg – gly-NH2), also a nonapeptide with a sulfur bridge, whose sequence differs from oxytocin by 2 amino acids. 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 synthesized by Vincent du Vigneaud in 1953, work for which he received the Nobel Prize in Chemistry in 1955.

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 (CRH) and dynorphin, for example, that act locally. The magnocellular neurons that make oxytocin are adjacent to magnocellular neurons that make vasopressin, and are similar in many respects.

Oxytocin receptor polymorphism

The oxytocin receptor in humans has several alleles, which differ in their effectiveness. Individuals homozygous for the "G" allele, when compared to carriers of the "A" allele, show higher empathy, lower stress response,[70] as well as lower prevalence of autism and of poor parenting skills.[71]

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[72], the homologs are further apart and transcribed in the same directions).

It is thought that the two genes resulted from a gene duplication event; the ancestral gene is estimated to be about 500 million years old and is found in cyclostomes (modern members of the Agnatha).[27]

Industrial use of drug

Oxytocin can be administered to bovine animals in order to increase the production of dairy milk.

Misuse of drug

Reports exist of hundreds of girls being kidnapped from across India and brought to Sodhawas and Geerwar villages in Alwar district of Rajasthan, where they are given oxytocin injections to hasten their puberty and pushed into prostitution. The kidnapped girls have reportedly been as young as six-month-old babies. They are raised by the villagers as their own daughters.[73]

See also

References

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  62. ↑ Gauquelin G, Geelen G, Louis F, Allevard AM, Meunier C, Cuisinaud G, Benjanet S, Seidah NG, Chretien M, Legros JJ (1983). "Presence of vasopressin, oxytocin and neurophysin in the retina of mammals, effect of light and darkness, comparison with the neuropeptide content of the neurohypophysis and the pineal gland". Peptides 4 (4): 509–15. doi:10.1016/0196-9781(83)90056-6. PMID 6647119. 
  63. ↑ Ang VT, Jenkins JS (April 1984). "Neurohypophysial hormones in the adrenal medulla". J. Clin. Endocrinol. Metab. 58 (4): 688–91. doi:10.1210/jcem-58-4-688. PMID 6699132. 
  64. ↑ Fields PA, Eldridge RK, Fuchs AR, Roberts RF, Fields MJ (April 1983). "Human placental and bovine corpora luteal oxytocin". Endocrinology 112 (4): 1544–6. doi:10.1210/endo-112-4-1544. PMID 6832059. 
  65. ↑ Geenen V, Legros JJ, Franchimont P, Baudrihaye M, Defresne MP, Boniver J (April 1986). "The neuroendocrine thymus: coexistence of oxytocin and neurophysin in the human thymus". Science 232 (4749): 508–11. doi:10.1126/science.3961493. PMID 3961493. 
  66. ↑ Amico JA, Finn FM, Haldar J (November 1988). "Oxytocin and vasopressin are present in human and rat pancreas". Am. J. Med. Sci. 296 (5): 303–7. doi:10.1097/00000441-198811000-00003. PMID 3195625. http://journals.lww.com/amjmedsci/Fulltext/1988/11000/Oxytocin_and_Vasopressin_Are_Present_in_Human_and.3.aspx. 
  67. ↑ Kukucka Mark A, Misra Hara P (1992). "HPLC determination of an oxytocin-like peptide produced by isolated guinea pig Leydig cells: stimulation by ascorbate". Arch. Androl. 29 (2): 185–90. doi:10.3109/01485019208987723. PMID 1456839. http://informahealthcare.com/doi/abs/10.3109/01485019208987723. 
  68. ↑ du Vigneaud V. (1960). "Experiences in the Polypeptide Field: Insulin to Oxytocin". Ann. NY Acad. Sci. 88 (3): 537–48. doi:10.1111/j.1749-6632.1960.tb20052.x. http://www3.interscience.wiley.com/journal/119764459/abstract. 
  69. ↑ Kukucka, Mark A. (1993-04-18). "Mechanisms by which hypoxia augments Leydig cell viability and differentiated cell function in vitro". Digital Library and Archives. http://scholar.lib.vt.edu/theses/available/etd-06062008-170416. Retrieved 2010-02-21. 
  70. ↑ Rodrigues SM, Saslow LR, Garcia N, John OP, Keltner D (December 2009). "Oxytocin receptor genetic variation relates to empathy and stress reactivity in humans". Proceedings of the National Academy of Sciences of the United States of America 106 (50): 21437–41. doi:10.1073/pnas.0909579106. PMID 19934046. 
  71. ↑ Angier, Natalie (2009-11-24). "The Biology Behind the Milk of Human Kindness". The New York Times. http://www.nytimes.com/2009/11/24/science/24angier.html. 
  72. ↑ Venkatesh B, Si-Hoe SL, Murphy D, Brenner S (November 1997). "Transgenic rats reveal functional conservation of regulatory controls between the Fugu isotocin and rat oxytocin genes". Proceedings of the National Academy of Sciences of the United States of America 94 (23): 12462–6. doi:10.1073/pnas.94.23.12462. PMID 9356472. PMC 25001. http://www.pnas.org/cgi/pmidlookup?view=long&pmid=9356472. 
  73. ↑ Bhalla, Abhishek; Choudhry, Preeti (2010). "Girls drugged into puberty, sold as prostitutes". India Today (India Today group) (May 27, 2010). http://indiatoday.intoday.in/site/Story/99132/120/Drugged+into+puberty,+sold+for+sex.html. 

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mepr

dsrd (o, p, m, p, a, d, s), sysi/, spvo

, drug(N5A/5B/5C/6A/6B/)
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phys/devp

mthr/fetu/infc,

proc, drug(2A/G2C)
Hypothalamic-pituitary hormones and analogues (H01)
Hypothalamic
GNRH
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END

anat/phys/devp/horm/cell

noco(d)//tumr, sysi/

proc, drug (A10/H1/H2//)
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trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, nrpr/grfr/), (, , ), , ; path (, , +, , , fsap, , )
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See also Template:Neuropeptides
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anat(h,r,t,,b,l,s)/phys/devp///nttm/

noco/auto/cong/tumr, sysi/, injr

proc, drug(N1B)
Tocolytics/labor repressants (G02CA)
β2-agonists
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Oxytocin antagonist
Atosiban
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Nifedipine
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Magnesium sulfate

: OBS

phys/devp

mthr/fetu/infc,

proc, drug(2A/G2C)