Category Archives: Obstetrics and Gynaecology

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.

Pregnancy: The Best Detox You Should Never Have.

 

In day-to-day conversation, announcing a pregnancy for a woman or couple can be met with happiness, congratulations, apprehension at times, and the simple acceptance that a baby is happily growing, awaiting a healthy arrival into the world. Difficulty conceiving, miscarriage, infertility and fertility treatments are topics that can remain unspoken for many during the time of announcing a pregnancy. For most women and men, their reproductive stories are rarely straight forward, interspersed with loss, contraception, relationship changes, careers, possibly illness and of course, absolute joy.
The journey of potential parenthood is often not straightforward. Practitioners of Complementary Medicine and those integrating this into their life are already aware just how important preconception care is for mothers and fathers to be. Preconception care should ideally take at least 6 months for both men and women, longer if specific health issues are of concern.

We already know that preconception care is essential to establish the following facets of health, ideally before conception takes place:

  • To identify and correct any maternal or paternal nutritional deficiencies
  • To identify and treat any unresolved illness in parents, as much as possible
  • To minimise or even eliminate exposure to environmental toxins, especially those affecting spermatogenesis (sperm production), oogenesis (egg production) and embryogenesis (development of the early embryo; first 12 weeks of gestation).
  • To eliminate exposure to environmental toxins known to accumulate in various human body tissue, for example, heavy metals.
  • Preconception care is essential to the health of all growing families, no matter the level of health experienced by parents. Preconception care maximises the nutritional status of both parents and stabilises the genome. Both allow for the transfer and inheritance of healthy genes. Though not a cure for profound heritable genetic disorders, preconception care can help to minimise some signs/symptoms in families for whom this is a problem.
  • Detoxification is a significantly important topic in preconception, prenatal and antenatal health. However, did you know just being pregnant induces a state of physiological detoxification in the mother? This topic is rarely discussed, even in complementary and orthodox medicine. This is a concern for a number of reasons:

1) Detoxification can actually be initiated very simply and effectively in the preconception phase; harsh methods are not required for its efficacy. It is an excellent form of preventive medicine. Detoxification should take place in the preconception phase, and ideally, well before conception.

2) Pregnancy (due to the action of the placenta) induces a state of physiological detoxification for the mother. Many health practitioners are unaware of the full extent of placental physiology, and the role of the placenta in maternal detoxification. A potential gap may exist in the education of practitioners with regards to this topic.

3) The health of a growing embryo and baby relies on lack of exposure to harmful environmental substances, PLUS those released from maternal tissue storage. They may inadvertently be exposed to such substances in utero, simply via healthy placental function.

The unknown process of pregnancy detoxification
The concept of pregnancy being a physiological process of detoxification remains relatively unknown. This is especially the case regarding general health information aimed at pregnant women. An internet or Google search looking for pregnancy as a form of detoxification will yield no results. The only information gleaned from such a search advises women not to undergo detoxification whilst pregnant or nursing. This advice is absolutely correct; detoxification can release substances stored in tissues that can be harmful to unborn babies, and infants or toddlers who are being breastfed. A closer examination of placental structure and function can explain the physiology behind this process.

The placenta is an exchange organ that requires sufficient and continual access to the maternal circulation. The establishment of such access is a critical process of the first trimester. Maternal erythrocytes (red blood cells, RBC’s) are present in the foetal circulation, though significant maternal RBC’s are not observed until 10-12 weeks gestation. Studies show conversions of blood vessel architecture in both the uterus and placenta toward the end of the first trimester. Additionally, glandular secretions from the uterus supply most nutrients (maternal proteins, carbohydrates and glycogen (from which glucose is derived) and lipids), plus non-nutrient growth factors of early pregnancy. This then progresses toward a more haemotrophic (blood derived) contribution as maternal arteries begin to supply nutrition. This process in essential in establishing a continual nutrient and energy supply for the growing foetus.

For a maternally derived molecule to access the foetal circulation, it must cross several layers of materno-placental tissues, which are selective and tend to regulate the passage of various substances to the foetus.

Placental anatomy and paternal genes
The formation of the placenta is truly remarkable; there is no other time in life when a human acquires a completely new organ, only to be expelled at the end of a pregnancy. The paternal genome of the baby’s father has a major influence on placental development; these genes preside over the building of the placenta. Thus, fathers are not exempt from preconception care practices. They provide half of their baby’s genetic material, and the majority of the genes required for building this vitally important organ.

Placental Physiology: metabolism, transfer and endocrine secretion
Put simply, the human placenta has three main roles during pregnancy:

1) To transfer nutrients (water, simple sugars, fatty acids, amino acids, vitamins, minerals and electrolytes) from mother to baby, via blood circulation. It is known as an exchange organ.

2) The synthesis of hormones, peptides (very small proteins) and steroids required to sustain growth. It functions as an endocrine organ.

3) Metabolism. Metabolic waste products from the baby are transferred in the same way to the mother for removal. It performs the waste removal functions of the lungs, the kidneys and the liver, all of which are immature in the developing foetus.

Pregnant women and babies in utero are exposed to a large variety of xenobiotic substances. The concept of the placenta acting as a complete physical barrier, protecting the foetus from all harm is false. It is known that most pharmaceutical drugs administered during a pregnancy cross the placenta to some extent. Specific chemical properties determine just how easily a substance can cross the placenta:

Chemical Properties

Lipid solubility: Highly lipid soluble molecules cross the placenta more easily. Some pharmaceutical drugs including aminoglycosides and some environmental toxins.

Protein binding: Non-protein bound substances cross the placenta more easily. They are biologically active and retain pharmacologic/toxic effect

Molecular weight: Low molecular weight substances cross the placenta more easily. Examples include many pharmacological agents. Any molecule < 900 daltons in size, Methylmercury, lead DDT and nicotine.

 

Physiological exchange from maternal to foetal circulation occurs via the following processes:

Passive diffusion: gases (O2, CO2, CO), H2O, H2O soluble vitamins cross faster than lipid soluble vitamins, glucose, small amounts of free fatty acids, electrolytes (Na+, K+, Cl-, Ca2+ and Mg2+). Diffusion occurs in both directions from mother to baby and the reverse.
Transport-protein mediated passage: solutes are transferred at a rate much greater than that of diffusion. Many amino acids are transported in this way.
Endocytosis and exocytosis: Endocytosis occurs when a maternally derived molecule is ‘trapped’ within a small pouch formed by specific placental cell membranes, forming a vesicle. The contents of these vesicles may then be released or ejected into the foetal environment via exocytosis. Antibodies, unconjugated steroid hormones and infectious agents (particularly viruses) readily cross the placenta via this transport mechanism.
Solvent drag/bulk flow: this drives water transfer, with water-soluble solutes being dragged along.
The placenta is a selective barrier and does prevent the passage of maternal hormones and other substances from crossing the placenta. Additionally, a cache of cytochrome P450 (CYP) enzymes (the same detoxification enzymes present in liver tissue) are active in placental tissue. These are more restricted than those observed in liver tissue, though several drugs and foreign substances are detoxified here.

“This combination of efflux transporters and defensive enzymes provides a degree of protection to the fetus against exposure to potentially noxious xenobiotics, although many drugs and chemicals can still cross and act as teratogens”.

– Burton, G. et al. Placental anatomy and physiology. In: Obstetrics: Normal and Problem Pregnancies, 7th ed. Elsevier.

Conclusion

Molecules that are without chemical charge, lipophilic (lipid-soluble), minimally protein bound and of a low molecular weight are known to cross the placenta to the foetal circulation. Some pharmaceutical drugs and environmental toxins belong to this chemical category. Many environmental toxins may have been stored in maternal adipose tissue before well before pregnancy, hence the importance of detoxification prior to conception and pregnancy. Some substances are known teratogens, harmful to growing babies and may also be linked to growth restriction. The enhanced elimination physiology of pregnancy is possibly beneficial for mothers, but undesirable for growing babies. The ideal situation is that any man and women of reproductive age where a pregnancy is possible should consider following:

1. Completely avoid nicotine and recreational drugs. Some substances are linked to foetal growth restriction and can be stored in adipose tissue long-term.

2. Assess exposure to environmental toxins via your occupation, residence, beauty/grooming practices or hobbies. Limit this exposure as best as you can.

3. Limiting environmental exposure is not practical 100% of the time. Nutritional, dietary and detoxification interventions with a professional health practitioner early in the preconception phase is an ideal way to minimise risk.

References

1. Syme M, Paxton J and Keelan J (2204). Clinical Pharmacokinetics.43: 487.
2. Myllynen P, Pasanen M and Vahakangas K (2007). The fate and effects of xenobiotics in human placenta. Expert Opinion in Drug Metabolism and Toxicology. 3(3):331-46.
3. Kozlowska R, Czekaj P. Ginekol Pol . Barrier Role of ABC facility of proteins in human placenta (2011). 82(1): 56-63.
4. Burton G, Sibley C and Jauniaux E. Placental anatomy and physiology. In: Obstetrics: Normal and Problem Pregnancies, 7th ed. Philadelphia: 2017; Elsevier, 2-25.
5. Castillo J and Rizack T. Special issues in pregnancy. In: Abeloff’s Clinical Oncology. 5th ed. Elsevier Churchill Livingstone; 2014, 914-25.

– See more at: https://kidshealth.com.au/pregnancy-best-detox-never/#sthash.wmbpsaeu.dpuf