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Oxytocin

Oxytocin

Annalies Corse BMedSc, BHSc

Masters Candidate (USYD).

Academic level paper: 5 minute read.

For clinicians and academics alike, research into oxytocin proves incredibly thought provoking, often presenting new questions and revealing new facts about this familiar yet evolving molecule. The physiological actions of Oxytocin extend over three medical science specialties: endocrinology, neurology and pharmacology. Novel research and findings regarding oxytocin are increasingly being published, with many of these discoveries reaching the general public. For clinicians, having a thorough and up to date understanding of oxytocin is important for clinical decision making, particularly in cases of pregnancy, postnatal health and emotional wellbeing of all individuals. Current research, basic chemistry, synthesis of oxytocin, conditions associated with reduced oxytocin levels and oxytocin in pregnancy are all important and relevant areas for the clinician to understand.

Basic chemistry 

Oxytocin is a nonapeptide hormone, consisting of a sequence of only nine amino acids (1). The name is derived from Greek terms meaning “swift birth”. It is very similar in amino acid sequence to the hormone, vasopressin (anti-diuretic hormone), differing only at residues 3 and 8 (1). The structural similarity between these two hormones is not surprising, as both are synthesised in the same region of the brain, the supraoptic and paraventricular nuclei of the hypothalamus (1).

Oxytocin is often colloquially referred to as the ‘love hormone’, due to its role in the establishment of complex social and bonding behaviors related to the reproduction and care of offspring. Oxytocin is produced in both males and females and facilitates reproduction in all vertebrates at several levels, though it does display physiological actions beyond reproduction (2).

Oxytocin-receptor binding requires both Mg2+ ions and cholesterol as regulators (2). Regulation of oxytocin release is also highly dependant on the correct flow of Ca2+ ions in to and out of oxytocin producing cells (2). Oxytocin receptors are located in areas of the brain associated with maternal behaviours, learning, memory and reinforcement (2).

Oxytocin and vasopressin have similar functions, and the genes responsible for the regulation of both are found on the same chromosome (1). Vasopressin appears to be associated with self-defence, vigilance, physical and emotional mobilisation (1). In contrast, oxytocin is related to “immobility without fear” (), inducing physiological states that are more relaxed, despite the presence of a stressor (childbirth being an example).

Oxytocin has been studied extensively in females. Many studies are in non-human animal models, though their mammalian physiology shares some similarities to human physiology. At the biochemical level, three major facts have been elucidated for Oxytocin:

  1. Stimulation of the Milk Ejection Reflex (MER). Smooth muscle cells containing oxytocin receptors surround alveoli within mammary tissue. Once stimulated by oxytocin, these smooth muscle cells contract, allowing the ejection of breast milk (3). The essential role of oxytocin in milk ejection has been confirmed in studies with oxytocin deficient mice.
  2. Stimulation of uterine smooth muscle during labour. Oxytocin receptors located on uterine smooth muscle tissue increase in number during later stages of gestation (3). Oxytocin facilitates the strong and prolonged uterine contractions required for parturition. The role for oxytocin here is far more complex. Evidence for the up regulation of oxytocin receptors in myometrial uterine tissue does exist. This usually occurs just prior to the onset of labour (2).
  3. Maternal behavioural traits. Successful reproduction in mammals requires mothers to become attached to, bond with and nourish their offspring, immediately following birth. Maternal oxytocin levels in cerebrospinal fluid (CSF) increase during parturition (1). Within neural brain tissue, oxytocin plays a major role in in establishing maternal behaviours and many oxytocinergic neurons are located throughout the central nervous system (2).

Oxytocin and males

In males, Oxytocin is also synthesised in the hypothalamus, but also the testes. Oxytocin is released in pulsatile form during male ejaculation (3, 4). Oxytocin is present in seminal fluid, and may facilitate the transport of sperm in both the male and female reproductive system (4). When examined in rats, Oxytocin is also a potent stimulator of spontaneous erections (4). In other animal studies, oxytocin appears to play a role in sexual satiety, as some male rodents display cessation of sexual activity for many days after oxytocin administration (3, 4). Thus, the complex role of oxytocin could not be more obvious, due to its potential role in both the soliciting and cessation of sexual behaviours in other animal studies. Oxytocin also modulates testosterone production, facilitating the conversion of testosterone to the more potent dihydrotestosterone (DHT) form (4).

How the body produces oxytocin

Oxytocin is synthesised in the hypothalamus, then transported to the posterior pituitary gland. The release of oxytocin into the body occurs either directly into the blood stream (via the posterior pituitary) or to other regions of the brain and spinal cord (1,2). There is also evidence that oxytocin is produced in peripheral tissues, including the uterus, placenta, amnion, corpus luteum, testis and heart (2). In cardiac tissue, oxytocin reduces the force of cardiac contractions, reduces heart rate and increases vasodilation (3).

The production and release of oxytocin is controlled by positive physiological feedback loops. Peripheral stimuli such as uterine contraction and infant suckling both stimulate further oxytocin release (5).

Ovarian tissue is a rather rich source of oxytocin, namely from the corpus luteum (5). The oxytocin gene is initially expressed during the preovulatory follicular phase (5). Some theories suggest that surging levels of Follicle Stimulating hormone (FSH) and Luteinising Hormone (LH) may directly or indirectly stimulate the biosynthesis of luteal oxytocin.

The epigenetic factors controlling expression of the oxytocin gene need to be studies and identified, in order to completely appreciate exactly how and why oxytocin is produced. Studies in non-human mammals have shown surging LH levels to be involved. Other bovine studies reveal that progesterone stimulates luteal oxytocin production (5). Some studies show the oxytocin gene can be stimulated by oestrogen, but this is not the case in all mammals (). An interesting piece of research from a nutritional biochemistry perspective is the ability of the human oxytocin gene to bind retinoic acid (5). This does suggest and support the already well-established role of retinoic acid in mammalian reproduction, but the exact relationship between retinoic acid and Oxytocin gene expression remains unknown. 

Current research

Oxytocin receptors have been identified in incredibly varied peripheral tissues, including renal, cardiac, thymic, adipose and pancreatic tissue (2, 6). While the precise reasons for these receptor locations are still being elucidated, other details reveal oxytocin to be far more than a pregnancy, love, or bonding hormone. One example in rats is the role of oxytocin as a cardiovascular hormone. In this situation, it acts in conjunction with vasopressin to facilitate both natriuresis and kaliuresis (6).

Other research on oxytocin examines its physiological role in social behaviours. While parental care and nursing are already linked to oxytocin, it appears social interaction, pair bonding, mate guarding, territorial aggression and mutual defence may also be attributable to the effects of oxytocin. All serve together to facilitate reproduction and are hallmark traits of all mammals (6, 7). The complexity of oxytocin action on social behaviour is highlighted by recent studies in monkeys, where the effect of exogenous oxytocin was dependant upon the social standing of each animal in the group. Already dominant males displayed increased aggression and sexual behaviours. Subservient males exhibited more associative and socially connected behaviours (6). Research since the 1990’s continues to show that breast feeding mothers remain more calm during stressful events than bottle feeding mothers, while other studies report oxytocin levels to be high in times of social isolation (6). The question remains if oxytocin operates differently depending upon its release after socially connective encounters, versus stressful experiences (7). Other feelings such as trust and behaviours such as generosity are possibly linked to oxytocin, however much of this research involves the administration of exogenous oxytocin, not the hormone in its natural state (7).

Intriguing research in human studies reveals oxytocin levels in early life may mediate certain social behaviours in adulthood. Urine levels of oxytocin in children raised with their biological parents were compared with children adopted from orphanages in Russia and Romania after contact with their mothers. Despite all the children living in caring homes, oxytocin levels only increased in children from biological families (7).

Other current areas of research include the ability of oxytocin to stimulate ghrelin secretion (8), thus suggesting Oxytocin may be involved in the physiology of hunger. Some studies have linked Oxytocin with the inhibition of tolerance to addictive drugs and a reduction in symptoms of withdrawal (9). As a novel form of oxytocin administration, inhaled oxytocin improved social interaction in people with autism (6, 7, 10). When released under stress free conditions, oxytocin appears to promote sleep. Researchers believe this may be due to a countering effect of oxytocin on cortisol (10). Some studies have actually shown sublingual Oxytocin administration can reduce cortisol levels (10).

Conditions associated with reduced Oxytocin levels

  • Diminished lactation. A lack of oxytocin in nursing mothers can diminish the MER and prevent lactation (5).
  • Post-partum depression (PPD) may be linked to reduced Oxytocin, though the mechanisms of PPD would involve multiple hormone cascades (5, 10).
  • Depressive and Anxiety disorders. Due to the clear role for Oxytocin in reducing maternal PPD and anxiety, it may be involved in affective disorders in males, children and non-pregnant females (7, 10). This is also the case for problematic socialisation in both children and adults.
  • Oxytocin may support thyroid function, as some experiments have shown Oxytocin can facilitate the incorporation of Iodine into thyroid tissue (11).
  • Fibromyalgia and other chronic pain syndromes. Recent evidence suggests healthy Oxytocin levels modulate nociception (12).
  • Oxytocin is being trialled in many forms of hormone replacement therapy, beyond standard oestrogen replacement (7).
  • Opioid drug abuse. A link between deficient Oxytocin production and opioid tolerance appears plausible, in both pharmaceutical and recreational drug use settings (9).
  • Breast cancer. Oxytocin is known to inhibit proliferation of certain breast cancer cell lines (11).

Oxytocin in pregnancy

Mammalian offspring are dependent on lactation from their mother’s for an extensive period after birth. The bonding that occurs after birth between mothers and new-borns is essential for the infants’ survival. Even if women do not do in to labour, give birth via caesarean section or cannot/choose not to breastfeed, strong bonding with babies can still occur. Fathers, adoptive parents and grandparents potentially form firm attachments with babies. All of these features suggest that simply the presence of an infant can initiate the release of oxytocin (3, 10). Oxytocin is not essential for parenting; however, healthy and sustained levels of oxytocin associated with childbirth may relieve anxiety (13). 

While all the physiological roles of oxytocin certainly remain unclear, it does appear to have dual purposes. In times of low-stress and eustress, oxytocin is certainly the ‘tend and befriend’ hormone, facilitating the formation of social bonds to maintain psychological well-being. Evidence of high oxytocin levels in times of stress may encourage people to seek social interactions, and is possibly involved in preventing decline of essential functions of the nervous system during times of immense fear and stress.

In a clinical setting, the administration of oxytocin as a medication only takes place in obstetrics, either during or very soon after childbirth. However, understanding the origins of Oxytocin synthesis and working with patients to prevent conditions/situations associated with reduced levels can only serve to promote wellness in both female, male and even infants and children in our clinical care. Both prenatal and postnatal support for mothers and fathers in a safe environment is essential for mental health. With respect to oxytocin, it certainly appears that emotional health has a huge impact on its physiological function, which in turn influences many physical health responses during life’s trying times.

(Originally written for and published by BioMedica Nutraceuticals).

References

  1. Open Chemistry Database. Oxytocin. National Centre for Biotechnology Information, US National Library of Medicine. Available at: https://pubchem.ncbi.nlm.nih.gov/compound/oxytocin#section=Information-Sources.
  2. Gimpl, G and Fahrenholz, F. (2001). The Oxytocin Receptor System: Structure, Function and Regulation. Physiological Reviews. 81 (2). 629-683.
  3. Evans J. (1997). Oxytocin in the Human– Regulation of Derivations and Destinations. European Journal of Endocrinology. 137 (6): 559-571.
  4. Sharma, D. et al. (2012). The ERβ ligand 5α-androstane, 3β,17β-diol (3β-diol) regulates hypothalamic oxytocin (Oxt) gene expression. Endocrinology. May; 153(5):2353-61.
  5. Stormshak, F. (2003). Biochemical and Endocrine Aspects of Oxytocin Production by the Mammalian Corpus Luteum. Reproductive Biology and Endocrinology. 1: 92.
  6. Carter, S. and Porges. S. (2013). The Biochemistry of Love: An Oxytocin Hypothesis. EMBO Reports. Jan; 14 (1): 12-16.
  7. Viero, C. et al. (2010). Oxytocin: Crossing the Bridge between Basic Science and Pharmacotherapy. CNS Neuroscience and Therapeutics. Oct; 16(5) e138-e156.
  8. Iwakura, H. et al. (2010). Oxytocin and Dopamine Stimulate Ghrelin Secretion by the Ghrelin-Producing Cell Line, MGN3-1 in Vitro. Endocrinology. 152 (7).
  9. McGregor, I. and Bowen, M. (2012). Breaking the Loop: Oxytocin as a Potential for Drug Addiction. Hormones and Behaviour. 61 (3). 331-339.
  10. Heinrichs, M. et al. (2003). Social Support and Oxytocin Interact to Supress Cortisol and Subjective Responses to Psychosocial Stress. Biological Psychiatry. Dec. 15; 54(12): 1389-98.
  11. Arturi, F. et al. (2005). Regulation of Iodide Uptake and sodium/iodide Symporter Expression in the mcf-7 Human Breast Cancer Cell Line. Journal of Clinical Endocrinology and Metabolism. 90 (4): 2321-2326.
  12. Goodin, B. et al. (2015). Oxytocin: A Multifunctional Analgesic for Chronic Deep Tissue Pain. Current Pharmaceutical Design. 21 (7): 906-913.
  13. Kirsch, P. et al. (2005). Oxytocin Modulates Neural Circuitry for Social Cognition and Fear in Humans. Journal of Neuroscience, 25 (49): 11489-11493.

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