Oxytocin is a hormone and a type of brain chemical. It is made in the hypothalamus and released by the back part of the pituitary gland. Oxytocin has been present in animals for a long time. In humans, it helps with behaviors such as forming social connections, feelings of love, reproduction, childbirth, and the time after childbirth. Oxytocin enters the bloodstream as a hormone during sexual activity and during childbirth. It can also be made into medicine. In both forms, oxytocin causes the uterus to contract, helping to speed up childbirth.

In its natural form, oxytocin also helps with bonding between a mother and child and the production of breast milk. The release of oxytocin is controlled by a process where its initial release causes more oxytocin to be made. For example, when oxytocin is released during a contraction of the uterus at the start of childbirth, this causes more oxytocin to be made, increasing the strength and frequency of contractions. This process continues until the activity that started it stops. A similar process happens during breastfeeding and during sexual activity.

Oxytocin is created by breaking down a larger protein made from the human OXT gene. Scientists have identified the structure of the active part of this hormone.

Etymology

The word "oxytocin" comes from the Greek words for "sharp" or "swift" and "childbirth." The adjective version, "oxytocic," describes medicines that help the uterus contract to speed up childbirth. Informally, oxytocin is called the "cuddle hormone," "hug hormone," or "love hormone" because it is linked to mating and social behavior. Studies have found that oxytocin plays a role in mating behavior in simple animals like C. elegans.

History

In 1906, British scientist Henry Hallett Dale discovered that a substance later named oxytocin helps the uterus contract. In 1910, Ott and Scott, and in 1911, Schafer and Mackenzie described how oxytocin helps release milk from the breasts. In 1909, William Blair-Bell first used oxytocin in patients to help with childbirth when complications occurred.

By the 1920s, scientists had separated oxytocin and vasopressin from pituitary tissue and gave them their current names. In 1952, researchers determined the molecular structure of oxytocin. In the early 1950s, American biochemist Vincent du Vigneaud found that oxytocin is made of nine amino acids and identified their order, making it the first polypeptide hormone to be sequenced. In 1953, du Vigneaud created the first synthetic version of oxytocin, also the first synthetic polypeptide hormone. He received the Nobel Prize in Chemistry in 1955 for this work. In the 1960s, Iphigenia Photaki studied different ways to make oxytocin and created hormone versions like 4-deamido-oxytocin.

Biochemistry

Estrogen helps increase the release of oxytocin and the number of oxytocin receptors in the brain. In women, a single dose of estradiol (a type of estrogen) can raise oxytocin levels in the blood.

Oxytocin and vasopressin are the only hormones from the human posterior pituitary gland that act far from where they are made. However, oxytocin-producing nerve cells also make other chemicals, such as corticotropin-releasing hormone and dynorphin, which work nearby. The nerve cells that make oxytocin are located close to those that make vasopressin and share many similarities.

The oxytocin peptide is first made as an inactive protein from the OXT gene. This protein includes another part called neurophysin I. The inactive protein is broken down into smaller pieces by enzymes, one of which is neurophysin I. The final step to create active oxytocin is done by an enzyme called peptidylglycine alpha-amidating monooxygenase (PAM).

The PAM enzyme needs vitamin C (ascorbate) to work properly. In experiments, sodium ascorbate alone was found to increase oxytocin production from ovarian tissue in a dose-dependent way. Many tissues where PAM and oxytocin are found, such as the ovaries, testes, eyes, adrenals, placenta, thymus, and pancreas, also store high amounts of vitamin C.

Oxytocin is broken down by an enzyme called oxytocinase, specifically leucyl/cystinyl aminopeptidase. Other enzymes can also break down oxytocin. Some chemicals, like amastatin, bestatin, leupeptin, and puromycin, stop oxytocin from being broken down, but they also affect other peptides, such as vasopressin and dynorphin A.

In the hypothalamus, oxytocin is made by specialized nerve cells in the supraoptic and paraventricular nuclei. It is stored in structures called Herring bodies at the ends of nerve cells in the posterior pituitary. Oxytocin is then released into the blood from the posterior pituitary. These nerve cells have branches that connect to the nucleus accumbens, a brain region with oxytocin receptors. The effects of oxytocin on the body and behavior are thought to be linked through these connections. Some oxytocin-producing nerve cells in the paraventricular nucleus send signals to other parts of the brain and the spinal cord. In some species, oxytocin receptors are also found in the amygdala and bed nucleus of the stria terminalis.

In the pituitary gland, oxytocin is stored in large, dense-core vesicles along with neurophysin I, as shown in the figure. Neurophysin I is a large piece of the original protein from which oxytocin is made.

The release of oxytocin from nerve endings is controlled by the electrical activity of oxytocin-producing cells in the hypothalamus. These cells send electrical signals down nerve fibers to the pituitary, where oxytocin-filled vesicles are released into the blood when nerve endings are activated.

Oxytocin levels in the brain are up to 1,000 times higher than in other parts of the body. Outside the brain, oxytocin-producing cells have been found in various tissues, including the corpus luteum and placenta in females, Leydig cells in the testes of males, and the retina, adrenal medulla, thymus, and pancreas in both sexes. The presence of oxytocin in these tissues raises questions about its role beyond the nervous system.

In some species, Leydig cells can make oxytocin on their own. This has been observed in rats (which make vitamin C internally) and guinea pigs (which need vitamin C from their diet). Oxytocin is also made by the corpus luteum in species like ruminants and primates. Along with estrogen, oxytocin helps trigger the production of a hormone called prostaglandin F2α, which causes the corpus luteum to shrink.

Most vertebrates have an oxytocin-like hormone that supports reproduction and a vasopressin-like hormone that helps regulate water balance. These two genes are usually close to each other on the same chromosome and are read in opposite directions. In some species, like fugu, the genes are farther apart and read in the same direction. Scientists believe these genes originated from a duplication of an older gene, which is about 500 million years old and found in cyclostomata (a group of ancient fish).

A 2023 study found that zebrafish use oxytocin when they sense fear from other fish. Fish that had their oxytocin production removed through gene editing could not respond to this fear. When oxytocin was injected back into these fish, they showed fear responses again, suggesting they may experience empathy. The study also found that the same brain regions involved in this behavior are present in mammals, indicating that oxytocin-based empathy may have evolved from a common ancestor millions of years ago.

Biological function

Oxytocin works in the body and in the brain. It acts through specific oxytocin receptors, which are a type of G-protein-coupled receptor called OT-R. These receptors need magnesium and cholesterol to function and are found in myometrial cells. They belong to a group of receptors known as rhodopsin-type (class I) G-protein-coupled receptors.

Research has shown oxytocin plays a role in behaviors such as orgasm, social recognition, pair bonding, anxiety, in-group bias, honesty, autism, and maternal behaviors. It may help reduce noise in the brain’s auditory system, improve recognition of social cues, and support focused social behavior. It might also increase reward responses. However, its effects depend on the situation, such as whether people are familiar or unfamiliar. Oxytocin also acts as a PAM for μ- and κ-opioid receptors, which may explain its pain-relieving effects.

Oxytocin’s effects in the body mainly come from the pituitary gland. Its influence on behavior likely comes from oxytocin neurons in the brain, which are different from those that connect to the pituitary gland. Oxytocin receptors are found in many brain and spinal cord regions, including the amygdala, ventromedial hypothalamus, septum, nucleus accumbens, and brainstem. Their distribution varies between species and changes during development, such as after childbirth in the montane vole.

Milk letdown reflex: In breastfeeding mothers, oxytocin causes milk to flow from the mammary glands into ducts, where it can be released through the nipple. Sucking by the baby sends signals to the hypothalamus, which triggers oxytocin release in bursts from the pituitary gland.

Uterine contractions: Oxytocin causes contractions during labor, helping the cervix open. It also causes mild contractions during breastfeeding, which help the uterus heal after childbirth. However, mice without oxytocin receptors have normal reproductive behavior and birth.

Erections and ejaculation: In male rats, oxytocin may help with erections. It is released during ejaculation in humans and other species, possibly aiding sperm release.

Sexual response: Oxytocin levels rise in the blood during sexual stimulation and orgasm in both men and women. Studies show oxytocin levels remain higher than normal for at least five minutes after orgasm. It may help move sperm and eggs by affecting muscle contractions.

Kidney function: Oxytocin slightly reduces urine excretion, similar to vasopressin. In some species, it increases sodium excretion, and high doses in humans may lead to low sodium levels (hyponatremia).

Heart function: Oxytocin and its receptors are found in the hearts of some rodents. It may help heart cells develop during embryonic stages, but its absence in knockout mice does not cause heart problems.

Stress response: Oxytocin can reduce the release of stress hormones like cortisol and adrenocorticotropic hormone, acting as an opposite to vasopressin in certain situations.

Fetal brain development: In rats, maternal oxytocin crosses the placenta and changes how GABA works in fetal brain cells, making them less active during birth and protecting them from damage.

Appetite regulation: Oxytocin neurons in the hypothalamus may suppress hunger. These neurons are missing in Prader-Willi syndrome, a condition linked to overeating and obesity. In starfish, a related chemical called asterotocin causes muscle relaxation and feeding-like behaviors.

Autism: Some studies suggest a link between oxytocin receptor gene mutations (OXTR) and autism. However, evidence for oxytocin’s effectiveness in treating autism is unclear, and results may be influenced by how studies are conducted.

Brain protection: Nasal oxytocin may help rats recover from stress-related learning issues by improving brain growth factors. In mice with early Alzheimer’s, oxytocin delayed memory loss and brain shrinkage. It may also reduce brain inflammation.

Pair bonding: In prairie voles, oxytocin released during sexual activity helps females form bonds with partners. Vasopressin may play a similar role in males. Oxytocin likely influences social behavior in humans, as shown by studies where both humans and dogs had higher oxytocin levels after petting.

Maternal behavior: Female rats given oxytocin-blocking drugs after birth do not care for their young. Virgin sheep, however, may act as mothers toward unfamiliar lambs after oxytocin is added to their spinal fluid.

Chemistry

Oxytocin is a type of protein made of nine amino acids (a nonapeptide) in the order: cysteine, tyrosine, isoleucine, glutamine, asparagine, cysteine, proline, leucine, glycine, and amide (Cys–Tyr–Ile–Gln–Asn–Cys–Pro–Leu–Gly–NH₂, or CYIQNCPLG–NH₂). The end of this molecule is changed into a primary amide, and a bond forms between the two cysteine molecules. Oxytocin has a molecular mass of 1007 Da, and one international unit (IU) of oxytocin equals 1.68 μg of pure peptide.

The structure of oxytocin is very similar in all placental mammals. However, in 2011, scientists found a new version of oxytocin in marmosets, tamarins, and other New World primates. Genomic studies showed a specific change in the oxytocin gene: a thymine replaced a cytosine, causing a single amino acid change at position 8 (proline instead of leucine). Since this discovery, other researchers confirmed this variant (Pro8-OT) and found additional oxytocin forms in these primates. For example, Vargas-Pinilla et al. identified variants with alanine, threonine, and valine at position 8, as well as a combination of valine at position 3 and proline at position 8. Ren et al. later found another variant with phenylalanine at position 2 in howler monkeys.

Recent improvements in scientific tools have made it easier to measure oxytocin levels using liquid chromatography (LC) combined with mass spectrometry (MS). Most studies use electrospray ionization (ESI) in positive mode, focusing on the parent ion [M+H] at a mass-to-charge ratio (m/z) of 1007.4. Diagnostic fragment ions at m/z 991.0, m/z 723.2, and m/z 504.2 are used to identify oxytocin. These findings helped develop current methods for measuring oxytocin with mass spectrometry.

Oxytocin has a structure similar to vasopressin. Both are nonapeptides with a single bond between two sulfur atoms. They differ in two amino acids: vasopressin has phenylalanine and arginine instead of isoleucine and leucine (bolded for clarity): Cys–Tyr–Phe–Gln–Asn–Cys–Pro–Arg–Gly–NH₂. Oxytocin and vasopressin were first isolated and synthesized in 1954. Vincent du Vigneaud received the 1955 Nobel Prize in Chemistry for this work, which included the first synthesis of a polypeptide hormone.

Oxytocin and vasopressin are the only hormones from the human posterior pituitary gland that act far from their source. However, oxytocin-producing neurons also make other peptides, such as corticotropin-releasing hormone and dynorphin, which work locally. Cells that make oxytocin are next to cells that make vasopressin. These are large neurons that can send electrical signals called action potentials.

In medicine

Drugs called small-molecule oxytocin receptor agonists, such as LIT-001, may help treat social challenges, like those seen in autism.