Original cartoon by Alex Martin
Source: Original cartoon by Alex Martin

Maternity wards routinely use synthetic oxytocin to kick-start the birth process and keep it moving. That is the main reason why this hormone is so widely known. It is less well known that, after birth, naturally produced oxytocin triggers milk ejection during breastfeeding. It is also connected with orgasms in both sexes and bonding between individuals. These additional links have spawned many labels for this multitasking hormone: "bonding hormone", “herding hormone”, “cuddle hormone”, “love hormone” and even “hormone of happiness”. Because oxytocin significantly affects the brain as well as reproductive organs, Heon-Jin Lee and colleagues aptly dubbed it “the great facilitator of life”.

Oxytocin in childbirth

Women giving birth in hospital are often given oxytocin intravenously, first to induce birth and then to reinforce contractions if needed during labour. Oxytocin also serves a crucial function straight after birth by promoting strong contractions that expel the placenta and reduce bleeding. This is a precarious time and post-partum hemorrhage is a principal cause of maternal mortality in societies with inadequate medical facilities.

Wikimedia Commons with acknowledgment to image author MindZiper
CPK model of the oxytocin molecule constructed using ACD/ChemSketch and Accelrys DS Visualizer.
Source: Wikimedia Commons with acknowledgment to image author MindZiper

Doubtless because of its significance for birth, but also because it is such a small molecule, oxytocin  —  a short chain of just 9 amino acids  —  was the first peptide hormone to be sequenced. (For comparison, insulin has 51 amino acids and haemoglobin chains in red blood cells each have over 140.) Vincent du Vigneaud sequenced and synthesized oxytocin in 1953, earning the Nobel Prize, and synthetic oxytocin is now in routine medical use. Since the digestive tract quickly degrades the hormone, it is usually injected into the bloodstream. More recently, because oxytocin cannot pass the blood-brain barrier, nasal sprays are often used to transfer the hormone directly to the brain along olfactory nerve cells.

Oxytocin and breastfeeding

In breastfeeding mothers, naturally produced oxytocin causes milk to flow through the “let-down reflex”. The hormone stimulates contraction of muscle cells around small milk-containing cavities, generating increased pressure that ejects milk through the nipple. As breastfeeding gets under way, the oxytocin surge can also spark womb contractions, often felt as after-pains that may be as strong as during labour. Oxytocin is initially released in response to the baby suckling, but later on it can be elicited by various stimuli, ranging from the sound of a baby crying to just thinking about breastfeeding.

Origins of oxytocin

Because oxytocin plays key roles in both birth and suckling, it might be thought that it originally evolved for those functions. But DNA sequences of genes in various animals have revealed a very different and rather surprising story. As so often happens during evolution, the oxytocin gene actually arose by duplication of a pre-existing gene. The original gene  —  directly next to the oxytocin gene  —  produces the hormone vasopressin. Just like oxytocin, vasopressin is a chain of nine amino acids. All but two of the amino acids are the same, yet the two hormones now play very different rôles in the body. The two main functions of vasopressin are constricting blood vessels and retaining body water. Like other placental mammals humans still have only a single oxytocin gene, but additional duplications have yielded three separate vasopressin genes.

Author’s original figure based particularly on information provided by Ocampo Daza et al. (2013)
Evolutionary tree showing initial duplication (D) of a vasopressin gene to yield an oxytocin gene at least 245 million years before before the origin of suckling (S) and almost 300 my before live birth (B).
Source: Author’s original figure based particularly on information provided by Ocampo Daza et al. (2013)

In two landmark papers in 2008 and 2009, Pai-Chung Gwee and colleagues compared DNA sequences of genes for oxytocin, vasopressin and related hormones across a wide range of animals with backbones (vertebrates). It emerged that all vertebrates with jaws (mammals, birds, reptiles, amphibians and various fishes including coelacanths), have at least one copy each of oxytocin and vasopressin genes. By contrast, vertebrates without jaws  —  lancelets and lampreys  —  have only a single gene that produces a hormone akin to vasopressin. This indicates that the duplication leading to separate genes for vasopressin and oxytocin occurred at some point after the basal split between jawed and jawless vertebrates, at least 435 million years ago. But that is long before suckling emerged in the common ancestor of mammals, around 200 million years ago. Indeed, pregnancy and live birth did not appear until the common ancestry of marsupials and placentals, some 145 million years ago. So the oxytocin gene clearly did not originate in connection with suckling or live birth.

Oxytocin and orgasm

In two papers published in 1987 and 1994, Marie Carmichael and colleagues reported that increases in circulating levels of oxytocin accompany orgasm in both men and women. Levels are markedly raised with orgasm attained through self-stimulation and the raised levels persist for several minutes. Carmichael and colleagues speculated that effects of oxytocin on muscle contraction might facilitate transport of eggs and sperms.

In an ingenious approach, German gynaecologist Ludwig Wildt and colleagues studied effects of synthetic oxytocin on sperm transport through a woman’s womb and oviducts. To achieve this, they deposited radioactively labelled sperm-sized albumin spheres deep in the vagina of 50 infertility patients and then tracked their progress with a detector. Labelled spheres reached the oviduct entrances just minutes after deposition, so the womb clearly acts like a pump. Intravenous injection of oxytocin was followed by a “dramatic” increase in the volume of spheres transported to the oviduct. Recording of pressure within the womb before and after oxytocin injection revealed an increase in muscle tone and strength of contractions, and the gradient was reversed to promote flow from the neck of the womb to the oviduct. This convincingly demonstrates that oxytocin promotes transport through the womb and oviducts.

Oxytocin and the brain

Oxytocin is not only connected with reproductive organs. It also contributes to brain function, particularly influencing social behaviour. Hence nicknames such as "bonding hormone", “love hormone” and “trust elixir”.

A now legendary example of oxytocin in action involves a stark contrast between two closely related vole species. Whereas prairie voles form lifelong pair bonds after an initial mating and subsequently share parental care, montane voles mate promiscuously and do not form lasting bonds. Research revealed that both oxytocin and vasopressin play a major part in triggering and maintaining the pair bond in prairie voles. Strikingly, if oxytocin and vasopressin are administered to montane voles, they also behave monogamously. In 2013, Hui Wang and colleagues demonstrated that blocking oxytocin and vaspressin receptors in a specific reward-and-pleasure centre of the brain in prairie voles prevents facilitation of partner preference. Injection of brain inhibitors and induction of pair-bonding by mating caused the same gene switching: truly a molecular basis for love.

It has also been shown in studies using nasal sprays that oxytocin can influence human social interactions. In one representative experiment reported in 2012, Dick Scheele, Onur Güntürkün and others showed that the hormone modulates social distance between men and women. A randomized trial of nasal administration of oxytocin with placebo controls revealed that, during an initial encounter with an attractive woman, men in a monogamous relationship are stimulated to keep a much greater distance than uncommitted men. This finding was confirmed with an approach/avoidance task involving photographs, in which oxytocin-primed men in a monogamous relationship approached pictures of attractive women more slowly. The authors suggested that oxytocin possibly helps to promote fidelity within human monogamous relationships.

So what was the initial function of oxytocin after that gene duplication over 435 million years ago? Our fishy ancestors swimming around in those primordial oceans doubtless led miserable, rather lonely lives. In addition to birth and suckling, we can also dismiss social life and orgasms. Logically, the only thing left is love  …………

References

Abrams, E.T. & Rutherford, J.N. (2011) Framing postpartum hemorrhage as a consequence of human placental biology: An evolutionary and comparative perspective. American Anthropologist 113:417-430.

Carmichael, M.S., Humbert, R., Dixen, J., Palmisano, G., Greenleaf, W. & Davidson, J.M. (1987) Plasma oxytocin increases in the human sexual response. Journal of Clinical Endocrinology & Metabolism 64:27-31.

Carmichael, M.S., Warburton, V.L., Dixen, J. & Davidson, J.M. (1994) Relationships among cardiovascular, muscular, and oxytocin responses during human sexual activity. Archives of Sexual Behavior 23:59-79.

Gwee, P.-C., Amemiya, C.T., Brenner, S. & Venkatesh, B. (2008) Sequence and organization of coelacanth neurohypophysial hormone genes: evolutionary history of the vertebrate neurohypophysial hormone gene locus. BMC Evolutionary Biology 8:93.

Gwee, P.-C., Boon-Hui Tay, B.-H., Brenner, S. & Venkatesh, B. (2009) Characterization of the neurohypophysial hormone gene loci in elephant shark and the Japanese lamprey: origin of the vertebrate neurohypophysial hormone genes. BMC Evolutionary Biology 9:47.

Lee, H.-J., Macbeth, A.H., Pagani, J.H. & Young, W.S. (2009) Oxytocin: the great facilitator of life. Progress in Neurobiology 88:127-151.

Magon, N. & Kalra, S. (2011) The orgasmic history of oxytocin: Love, lust, and labor. Indian Journal of Endocrinology & Metabolism 15(Suppl. 3):S156-S161.

Ocampo Daza, D., Lewicka, M. & Larhammar, D. (2013) Phylogenetic analyses of the vertebrate oxytocin and vasopressin receptor gene family. General and Comparative Endocrinology 175:135-143.

Scheele, D., Striepens, N., Güntürkün, O., Deutschländer, S., Maier, W., Kendrick, K.M. & Hurlemann, R. (2012) Oxytocin modulates social distance between males and females. Journal of Neuroscience 32:16074-16079.

Wang, H., Duclot, F., Liu, Y., Wang, Z. & Kabbaj, M. (2013) Histone deacetylase inhibitors facilitate partner preference formation in female prairie voles. Nature Neuroscience 16:919-924.

Wildt, L., Kissler, S., Licht, P. & Becker, W. (1998) Sperm transport in the human female genital tract and its modulation by oxytocin as assessed by hysterosalpingoscintigraphy, hysterotonography, electrohysterography and Doppler sonography. Human Reproduction Update 4:655-666.

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