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A comfortable birth

27 September 2006

How does the body respond to modern day medicinal drugs?

Since the dawn of man, or more specifically the dawn of woman, we have populated our planet through the natural wonder of childbirth. Nobody ever said that this would be an easy-going, painless, stress-free process; in fact due to the hardships of labour, the death of both mother and child has been an expected tragedy for the majority of our time here on Earth. There has never been a better time to give birth than the present day. Modern medicine provides us with well-equipped hospitals, advanced technologies and an array of drugs that all help to make labour a more comfortable and safer experience. Andrés López Bernal devotes his time researching ways by which one particular drug, commonly used during labour, can be made more effective.

The drug itself is actually a hormone called oxytocin that is produced naturally in the body and, when released from the pituitary gland, stimulates the contraction of the uterus. Oxytocin can therefore be used to induce and augment labour, enabling the labour process to be managed to suit the individual. It is administered intravenously and the rate of infusion is increased until strong labour (three contractions every 10 minutes, each lasting more than 40 seconds) is reached. Although its use as a labour management drug is well established, responses to oxytocin infusion remain variable and unpredictable among women. Continuous infusion of oxytocin  does not necessarily induce strong labour and, in the worst cases, can cause foetal distress and uterine rupture.

What then, can be done to improve the way oxytocin acts within the body?

The human body responds to stimuli, be it external or internal, by activating a variety of cellular processes. These processes are controlled and switched on and off through what are called molecular signalling pathways. In the case of oxytocin, when it is released or infused into the body it binds to receptors on the surface of cells. This starts the signalling cascade and cellular processes that will lead to the muscle of the uterus contracting. These are the contractions that most women feel as they realise that they are about to give birth to the child they have been carrying for the past nine months.

Professor López Bernal’s research investigates the specific receptor on the cell’s surface that recognises oxytocin and reacts on exposure to it. Through understanding the molecular mechanisms by which the receptor works, he hopes to apply this knowledge and make the use of oxytocin during labour more efficient.

Receptors on the surface of cells are made from protein. The oxytocin receptor (OTR) is a certain class of receptor know biochemically as a ‘G-protein coupled receptor’. These receptors are involved in all types of stimulus-response pathways and are the target of many modern medicinal drugs. They are well studied and a lot is already known as to how they work. Lopez Bernal suggests that like other G-protein coupled receptors, the OTR desensitizes and/or internalizes upon continuous exposure to oxytocin. This means that the OTR either effectively stops producing a signal – even when oxytocin is bound to the OTR – or it moves inside the cell, where it is unable to detect the oxytocin. A greater understanding of which mechanism occurs when would enable better protocols to be developed for the pharmacological use of oxytocin during labour and other periods of pregnancy.

In one piece of research López Bernal and colleagues are able, for the first time, to demonstrate the importance of a particular signalling pathway and clarify the role of certain proteins involved in OTR internalization and desensitization. Using a human embryonic kidney cell line, they showed that both internalization and desensitization of the OTR upon drug exposure was significantly reduced when certain proteins involved in these processes were mutated; ie, not functioning properly. Through understanding the role of these proteins, we can gain a better idea of how oxytocin should be administered during labour.

One particular group of proteins (beta-arrestins) identified as being involved in the desensitization of the OTR, are suggested to be important for the removal of the receptor from the surface of the cell. Lopez Bernal aims to better understand OTR regulation by the study of proteins like these and to demonstrate novel mechanisms by which oxytocin regulates its own receptors and hence uterine sensitivity.

Whilst the identification and clarification of molecular signalling pathways and proteins will build a much-needed foundation for future improvements in the way oxytocin is administered to women in labour, are there any immediate applications for López Bernal’s findings? Yes. Experimental results show that internalisation of the OTR in response to oxytocin exposure is very rapid and in the short term the OTR becomes desensitised to the oxytocin hormone. This research suggests that the continuous infusion of oxytocin to stimulate and strengthen contractions may not be the most optimal approach but that a timed short dose, corresponding to the length of time in which the oxytocin receptor is desensitized, may be more effective. However this requires further testing by controlled clinical trials.

So what does this mean for expectant mothers and their newborn babies?

Ultimately it will enable labour to be managed to suit the individual, and allow for better hospital care. Your oxytocin will be administered as you require, making it safer for you and your baby. Women who have a higher risk of uterine-rupture stand to benefit the most from more efficient oxytocin dosages.

If we continue to elucidate the molecular mechanisms for how cell receptors work, this could not only have a deep impact on the effective administration of oxytocin, but many other medicinal drugs which rely on biochemical receptors could also reach their potential for successful, safe treatments.

Andrés López Bernal/Obstetrics and Gynaecology

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