The impact of metformin on early placental development and metabolism
Lead Research Organisation:
University of Cambridge
Department Name: Obstetrics and Gynaecology
Abstract
Healthy pregnancies are fundamental to healthy populations, but very few therapies to improve pregnancy outcomes are available. In particular there are few drugs that can prevent frequent complications of early pregnancy, such as miscarriage and early-onset pre-eclampsia. Some evidence suggests metformin might help to prevent both of these outcomes. Metformin is a cheap, globally available drug, with few serious side-effects. If it were shown to be effective for preventing miscarriage or pre-eclampsia, then this would be a major breakthrough for early pregnancy care and it could be made available to women at risk globally. Both miscarriage and pre-eclampsia can be caused by problems very early in the development of the placenta, which supports the developing baby the whole way through pregnancy. Tiny variations in placental development at the start of pregnancy can lead to catastrophic failure later on, so optimal establishment of placentation is crucial to reduce the risk of later complications. We aim to investigate whether metformin improves the chances of the placenta establishing correctly during these early stages. Our previous work suggests that metformin may counteract the impact of too much oxygen or glucose during placental development and thus improve the chances of the placenta being able to support the growing fetus most effectively.
However there is also concern metformin may be detrimental to the placenta later in pregnancy. Our meta-analysis suggests that mothers treated with metformin are more likely to give birth to smaller babies, suggesting that metformin may restrict fetal growth during late pregnancy. Evidence also suggests that these babies may go on to accumulate more fat tissue in later life. Our previous work shows that metformin alters the way that the placenta generates energy and the fuels that it uses to support the developing baby. In view of these findings, the precise ways that metformin acts on the developing placenta need careful evaluation before considering whether it could safely and effectively be used to prevent miscarriage or pre-eclampsia.
We will examine in detail whether metformin might alter the processes of energy production, growth, and the formation of different cell types that are all vital to normal placental development. We will take advantage of an exciting new development in pregnancy research, the mini 'placenta-in-a-dish' (trophoblast organoids). These tiny cell clusters divide and form into all the major cell types of the placenta, allowing us to study these processes in the laboratory. We will also use established human trophoblast stem cell lines to optimise our experiments, validate our findings, and perform additional assays.
Our key experiments will involve measuring the effect of metformin at clinically-relevant doses on the growth and development of the early placenta, in particular the formation of cells that establish contact with the mother's circulation. We hypothesise that metformin will influence the ability of these cells to differentiate and form adequate connections. We will also alter oxygen levels and glucose levels in our experimental placenta-in-a-dish models. Placental development occurs naturally at very low oxygen levels inside the womb initially, and exposure to excess oxygen from the mother's blood is thought to be a cause of early pregnancy complications. We will investigate whether metformin can prevent damage to the developing cells from excess oxygen, by blocking the formation of free radicals. We will also look at the impact of glucose concentrations during early development and whether cell energy balance can be maintained in the presence of both metformin and physiologically low glucose levels. Our over-arching aim is to establish whether metformin could be a safe and effective drug to help prevent early pregnancy complications.
However there is also concern metformin may be detrimental to the placenta later in pregnancy. Our meta-analysis suggests that mothers treated with metformin are more likely to give birth to smaller babies, suggesting that metformin may restrict fetal growth during late pregnancy. Evidence also suggests that these babies may go on to accumulate more fat tissue in later life. Our previous work shows that metformin alters the way that the placenta generates energy and the fuels that it uses to support the developing baby. In view of these findings, the precise ways that metformin acts on the developing placenta need careful evaluation before considering whether it could safely and effectively be used to prevent miscarriage or pre-eclampsia.
We will examine in detail whether metformin might alter the processes of energy production, growth, and the formation of different cell types that are all vital to normal placental development. We will take advantage of an exciting new development in pregnancy research, the mini 'placenta-in-a-dish' (trophoblast organoids). These tiny cell clusters divide and form into all the major cell types of the placenta, allowing us to study these processes in the laboratory. We will also use established human trophoblast stem cell lines to optimise our experiments, validate our findings, and perform additional assays.
Our key experiments will involve measuring the effect of metformin at clinically-relevant doses on the growth and development of the early placenta, in particular the formation of cells that establish contact with the mother's circulation. We hypothesise that metformin will influence the ability of these cells to differentiate and form adequate connections. We will also alter oxygen levels and glucose levels in our experimental placenta-in-a-dish models. Placental development occurs naturally at very low oxygen levels inside the womb initially, and exposure to excess oxygen from the mother's blood is thought to be a cause of early pregnancy complications. We will investigate whether metformin can prevent damage to the developing cells from excess oxygen, by blocking the formation of free radicals. We will also look at the impact of glucose concentrations during early development and whether cell energy balance can be maintained in the presence of both metformin and physiologically low glucose levels. Our over-arching aim is to establish whether metformin could be a safe and effective drug to help prevent early pregnancy complications.
Technical Summary
Metformin exposure during early pregnancy has become widespread globally, particularly in the context of fertility treatment and polycystic ovarian syndrome, with observational evidence suggesting that it reduces the risk of both miscarriage and pre-eclampsia. Early placental development is a key driver of these pregnancy complications, hence we will investigate how metformin exposure affects (i) extravillous trophoblast (EVT) differentiation and invasion, and (ii) placental energy production and metabolism during early pregnancy (<9wks).
We have recently shown that metformin (at clinically-relevant concentrations) reduces mitochondrial oxygen utilisation in cultured primary human trophoblasts and thus limits the potential for ROS generation, reducing oxidative stress. We therefore hypothesise that metformin may be protective from early excess oxygen exposure during EVT differentiation by preventing oxygen conversion to ROS. We have also shown that metformin decreases ATP production, despite partial compensation from upregulation of glycolysis. Our preliminary data demonstrates that the central metabolic regulator AMPK is activated by metformin in first trimester trophoblasts. NOTCH1 signalling via AMPK may thus be a further pathway by which metformin promotes EVT differentiation and invasion.
We will use two model systems, (i) human trophoblast stem cells, and (ii) trophoblast organoids, to investigate the impact of metformin under a physiological and supra-physiological concentrations of oxygen and glucose on early placental differentiation (using time-lapse imaging), energy production (by assaying cellular oxygen consumption rate and respiratory chain complex activities) and metabolism (via substrate utilisation assays). Our over-arching aim is to investigate whether metformin improves the establishment of early placentation, and hence could provide effective prophylaxis against early pregnancy complications for individuals at high risk.
We have recently shown that metformin (at clinically-relevant concentrations) reduces mitochondrial oxygen utilisation in cultured primary human trophoblasts and thus limits the potential for ROS generation, reducing oxidative stress. We therefore hypothesise that metformin may be protective from early excess oxygen exposure during EVT differentiation by preventing oxygen conversion to ROS. We have also shown that metformin decreases ATP production, despite partial compensation from upregulation of glycolysis. Our preliminary data demonstrates that the central metabolic regulator AMPK is activated by metformin in first trimester trophoblasts. NOTCH1 signalling via AMPK may thus be a further pathway by which metformin promotes EVT differentiation and invasion.
We will use two model systems, (i) human trophoblast stem cells, and (ii) trophoblast organoids, to investigate the impact of metformin under a physiological and supra-physiological concentrations of oxygen and glucose on early placental differentiation (using time-lapse imaging), energy production (by assaying cellular oxygen consumption rate and respiratory chain complex activities) and metabolism (via substrate utilisation assays). Our over-arching aim is to investigate whether metformin improves the establishment of early placentation, and hence could provide effective prophylaxis against early pregnancy complications for individuals at high risk.
