Prematurity is the no. 1 cause of infant death and disability worldwide, in children under 5 years
Extending pregnancies by even 1 week would save the NHS £265million per year
In the UK, only 50% of babies born at 24 weeks survive
The causes of preterm labour are still unknown
Once preterm labour has started it’s too late, we cannot stop it
HOW PROGESTERONE WORKS
To date, our work on progesterone has challenged the widely-accepted view of how the hormone works. We are continuing to analyse how it interacts with the onset of labour to learn how it can be used as a potential treatment.
cAMP molecule combined with progesterone could help women in labour.
Our current work has shown that progesterone exerts most of its anti-inflammatory/pro-gestational effect via the glucocorticoid receptor. Further, we have shown that its action is through repression of a major pro-inflammatory network called the AP-1 system. This paper has now been published in Molecular Endocrinology. This work directly contradicts the current accepted version of events, which had progesterone acting via the progesterone receptor to inhibit the NFkB system. Our work changes the paradigm of progesterone action in pregnancy and opens a completely new avenue of research.
Future work We will define the effect of progesterone-glucocorticoid receptor action, both in terms of where progesterone acts and how this effect is reversed with the onset of labour. We have also shown that the intra-cellular signalling molecule, cAMP, increases progesterone action that could help prevent the onset of labour.
We have also studied the effect of cAMP as an anti-inflammatory agent and shown that it is highly effective, supporting our proposal to use a cAMP agonist in combination with progesterone. Additionally, we have investigated how cAMP enhances progesterone action and how it mediates its anti-inflammatory effects and now have novel data, which is due to be submitted for publication shortly.
These findings are being translated into a clinical trial of cAMP in women at high risk of preterm labour in our Borne/AMR funded clinical trial of aminophylline and progesterone.
UNDERSTANDING POTENTIAL TREATMENTS
Investigating the effects of progesterone allows us to see how it affects pregnancy and may be used as a potential treatment.
Our Borne scientists are working towards the same goal: prevent preterm birth.
We know that progesterone is essential for the maintenance of pregnancy. However, what is less clear is whether increasing the levels of progesterone reduces the risk of preterm labour in high-risk pregnancies. Several papers have reported benefit and others no effect, but the studies have used different doses of progesterone, given via different routes in different groups of at-risk pregnant women.
These studies may have been premature, since there are outstanding questions that should have been addressed before these studies were carried out: Some models support the concept that progesterone is essential for the maintenance of human pregnancy, but we still do not know how progesterone acts. Further, it seems very likely that there are several causes of preterm labour and each probably acts through a distinct pathway.
Consequently, until we understand what these processes are and how to identify distinct groups of at-risk women we will not be able to identify effective treatments or target their use.
It is highly unlikely that one treatment will be effective in all at risk women.
Our work on progesterone seeks to understand how progesterone works. This is important not only to understand the action of progesterone, but also because this knowledge will of itself help us to understand how human pregnancy is maintained. Once the mode of action of progesterone is clear, we will research methods to modulate its action.