Oxytocin is a peptide hormone and neuropeptide normally produced in the hypothalamus and released by the posterior pituitary. Present in animals since early stages of evolution, in humans it plays roles in behavior that include social bonding, love, reproduction, childbirth, and the period after childbirth. Oxytocin is released into the bloodstream as a hormone in response to sexual activity and during childbirth. 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 maternal bonding and milk production. 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 uterine contraction at the start of childbirth, this stimulates the production and release of more oxytocin and an increase in the intensity and frequency of contractions. This process intensifies in 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:
Etymology The term "oxytocin" derives from the Greek (), based on (), meaning "sharp" or "swift", and (), meaning "childbirth". The adjective form is "oxytocic", which refers to medicines that stimulate uterine contractions, to speed up the process of childbirth. Colloquially, it has been referred to as the "cuddle hormone," "hug hormone," or "love hormone" because of extensive evidence of its involvement in mating and social behavior. It is involved in mating behavior in animals as low as C. elegans.
History The uterine-contracting properties of the principle that would later be named oxytocin were discovered by British pharmacologist Henry Hallett Dale in 1906, and its milk ejection property was described by Ott and Scott in 1910 and by Schafer and Mackenzie in 1911. In 1909 the first clinical use of oxytocin was performed by William Blair-Bell to induce childbirth in patients with complications.
By the 1920s, oxytocin and vasopressin had been isolated from pituitary tissue and given their current names. Oxytocin's molecular structure was determined in 1952. In the early 1950s, American biochemist Vincent du Vigneaud found that oxytocin is made up of nine amino acids. He identified its amino acid sequence, the first polypeptide hormone to be sequenced. In 1953, du Vigneaud carried out the synthesis of oxytocin, the first polypeptide hormone to be synthesized. Du Vigneaud was awarded the Nobel Prize in Chemistry in 1955 for his work. 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.
Biochemistry
Biosynthesis 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 neurons that make oxytocin are adjacent to magnocellular neurons that make vasopressin and are similar in many respects.
The oxytocin peptide is synthesized as an inactive precursor protein from the OXT gene. This precursor protein also includes the oxytocin carrier protein neurophysin I. 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).
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. 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.
Oxytocin is known to be metabolized by the oxytocinase, leucyl/cystinyl aminopeptidase. Other oxytocinases are also known to exist. 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.
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 neurons in the nucleus accumbens, a brain structure where oxytocin receptors are expressed. 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. Oxytocin is also produced by some neurons in the paraventricular nucleus that project to other parts of the brain and to the spinal cord. 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.
The electrical activity of the oxytocin cells in the hypothalamus regulates the secretion of oxytocin from the neurosecretory nerve endings. 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 are as much as 1000-fold higher than peripheral levels. Outside the brain, oxytocin-containing cells have been identified in several diverse tissues, including in females in the corpus luteum and the placenta; in males in the testicles' interstitial cells of Leydig; and in both sexes in the retina, the adrenal medulla, the thymus and the pancreas. 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.
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 in their diets. 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.
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 (fewer than 15,000 bases apart) on the same chromosome. They are transcribed in opposite directions (however, in fugu, 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).
A 2023 study found that zebrafish utilize oxytocin in reaction to the fear of other fish. It found that zebrafish oxytocin production, removed by gene editing, cannot respond to the fear of other fish. When oxytocin is injected back into the fish, they react again, suggesting they may have empathy regarding this emotion. Furthermore, because the same brain regions are involved as in mammals, the study suggests oxytocin-based empathy may have evolved from a common ancestor many millions of years ago.
Influences
A variety of circumstances and drugs have been found to affect oxytocin levels in humans.
Labor, breastfeeding, pregnancy, hypoglycemia, sexual self-stimulation, physical activity, and psychosocial stress all increase oxytocin levels in humans. Oxytocin levels increase 3- to 4-fold during pregnancy and increase a further 3- to 4-fold during labor. They also increase by 5-fold during breastfeeding. In premenopausal women, oxytocin levels are almost twice as high during ovulation and the luteal phase than during the follicular phase. Oxytocin levels are higher, by about 2-fold, in new romantic relationships. Levels of oxytocin are lower in underweight women with anorexia nervosa, returning to normal with recovery.
Estrogens such as estradiol and ethinylestradiol have been found to dose-dependently and robustly increase oxytocin levels in humans. In addition, they have been found to increase the expression of the oxytocin receptor in the brain. Controlled ovarian hyperstimulation can increase estradiol levels by around 90-fold and oxytocin levels by about 6.5-fold. Increased estrogen levels are thought to be involved in the increases in oxytocin levels during the ovulatory and luteal phases, during pregnancy, and in the premenopause compared to the postmenopause. Whereas estrogens unambiguously stimulate oxytocin production, findings appear to be mixed on the influence of androgens such as testosterone on oxytocin production and oxytocin receptor expression. However, dihydrotestosterone (DHT) metabolites acting as estrogen receptor beta (ERβ) agonists such as 3β-androstanediol may stimulate oxytocin production similarly to estrogens like estradiol.
The entactogen MDMA, which is a serotonin–norepinephrine–dopamine releasing agent (SNDRA), strongly increases oxytocin levels in humans, by 4- to 8-fold. This appears to play a key role in the drug's entactogenic effects, including its euphoria, enhanced empathy, and reduced anxiety. Stimulants like dextroamphetamine, methamphetamine, methylphenidate, and modafinil, with are catecholamine releasing agents and/or reuptake inhibitors, do not affect oxytocin levels in humans. However, in another study, methamphetamine increased oxytocin levels during dyadic conversations, albeit to a lesser extent than MDMA. 4-Fluoroamphetamine, which shows greater serotonin release than amphetamine or methamphetamine, increases oxytocin levels in humans. The serotonin–norepinephrine releasing agent (SNRA) fenfluramine increases oxytocin levels in humans as well. Serotonergic psychedelics including LSD, psilocybin, mescaline, and dimethyltryptamine (DMT) have been found to increase oxytocin levels in humans, though with much smaller increases in levels than MDMA. The serotonin 5-HT1A receptor agonist buspirone does not affect oxytocin levels in humans, though it augmented the increase in oxytocin levels in response to hypoglycemia.