Is pre-eclampsia an endometrial disorder?

Graham Burton, FMedSci 

Director of Centre for Trophoblast Research

University of Cambridge 

Pre-eclampsia is a syndrome defined by unique diagnostic criteria laid down by the ISSHP, but is just one of a number of complications of pregnancy that share a common pathophysiology centred around poor placentation, including miscarriage, fetal growth restriction and premature delivery. Deficient invasion of the uterine wall by placental trophoblast cells following implantation results in incomplete remodelling of the spiral arteries, and consequently malperfusion of the placenta. The severity of the deficit determines the clinical outcome, although there are powerful interactions with the maternal genome. This is well illustrated in pre-eclampsia where it is now clear that there are at least two distinct sub-types, with possibly more to be identified. Early-onset pre-eclampsia is acknowledged to be primarily a placental problem, with extensive gross and molecular pathologies causing the release of pro-inflammatory and anti-angiogenic factors into the maternal circulation. By contrast, in late-onset pre-eclampsia the placenta is often indistinguishable from normotensive controls, and evidence of malperfusion is minimal. Instead, it is thought that in these cases the individuals carry a genetic predisposition to cardiovascular disease, causing them to be oversensitive to lower levels of factors released from a relatively normal placenta. Whilst often presented as polar causations, in reality, the balance between the placental and maternal component is likely to vary across the spectrum of gestational age at clinical presentation.

 

Placental development in the human is precocious and starts at the time of implantation around day 7 post-conception. By day 11 the conceptus is embedded within the superficial endometrium, and by the end of the following week early placental villi cover the entire surface of the gestational sac. The villi merge at their tips to create the trophoblastic shell that encapsulates the conceptus and forms the interface with the maternal tissues. It is essential that a robust shell is formed, as it seals off the conceptus and protects it from excessive levels of oxygen and xenobiotics during the critical phase of organogenesis ¹. The shell is also the source of the trophoblast cells that will remodel the spiral arteries, and so any impairment of its development will likely be reflected in deficient arterial remodelling. If we are to understand the pathology underlying early-onset pre-eclampsia and related conditions, we need to have a greater knowledge of the placental-endometrial interactions that support and stimulate this rapid growth of the placenta, and the formation of the shell. These are difficult areas to research systematically for several reasons; some of the key events will have taken place before an individual realises they are pregnant, the implantation site is inaccessible and investigations are limited for obvious ethical reasons, and there is a lack of suitable animal models. Placental bed biopsies provide insights into the end-stage pathology at the time of delivery, but yield little information regarding events that took place six to nine months earlier. Equally, until very recently, the lack of a human trophoblast stem cell restricted in vitro experiments on trophoblast proliferation and invasion to the use of choriocarcinoma or trophoblast-like cell lines that are karyotypically abnormal or often a mix of trophoblast and mesenchymal cells.

 

Despite these difficulties, progress has been made. It is now appreciated that the maternal circulation to the placenta is only fully established towards the end of the first trimester, and that before 10 weeks the conceptus is supported by secretions from the endometrial glands, so-called histotrophic nutrition or ‘uterine milk’ ². These secretions are delivered into the cavity of the placenta, where they bathe the early villi and are taken up by the trophoblastic epithelial covering. Rich in carbohydrates and lipids, the secretions provide a source of energy and nutrients to support rapid cell proliferation. The secretions also contain a variety of growth factors that when applied exogenously to placental explants stimulate proliferation of the trophoblast cells ³. Manipulations of endometrial gland development in animal models have shown that the secretions are essential for early development of the conceptus ⁴. Excitingly, it has also been shown that the trophoblast is able to signal to the glands and upregulate expression of the growth factors, including epidermal growth factor and fibroblast growth factor that are required for maintenance of trophoblast stem cells ⁴. The placenta is therefore able to stimulate its own development through a dialogue involving the decidua and the endometrial glands, which represents a fascinating biological paradigm.

 

Is there any evidence that such a mechanism operates in the human? If so, could deficiencies in the dialogue lead to poor development of the maternal-fetal interface that manifests as early-onset pre-eclampsia or other complications? Circumstantial evidence suggests that this may be the case. The endometrial gland cells display the same array of endocrine receptors as are expressed in animal species, and pathologists have long recognised the hypersecretory phenotype that the glands adopt in early pregnancy, the so-called Arias-Stella reaction. Lower levels of glycoproteins secreted by the glands, such as glycodelin-A, have been linked to miscarriage, when it is known that in 70% of cases formation of the trophoblastic shell is incomplete ¹. Furthermore, microarray analysis of chorionic villus samples from patients that went on to develop pre-eclampsia show aberrant expression of decidual, rather than placental, genes ⁵.

 

A major opportunity for more detailed investigation of the mechanism is provided by the derivation of organoids of the endometrial glands ^{6, 7}. These 3-D cultures faithfully replicate the transcriptome of glands in vivo, and importantly upregulate the secretion of uterine milk proteins in response to early pregnancy hormones ⁶. Study of these organoids will enable the signalling pathways involved to be fully elucidated, and the composition of the secretions to be determined. The establishment of these cultures promises to shed light on one of the ‘black boxes’ of early pregnancy, the initial stages of placental development following implantation. If the arguments presented here are correct, then research should focus on events during the periconceptional period, and public health should aim to ensure that the endometrium, the soil into which the conceptus implants, is in the optimum and most fertile state prior to conception.  In this way we may be able to reduce the incidence of not just early-onset pre-eclampsia, but other complications on the same spectrum of defective placentation.

 

1. Burton GJ, Jauniaux E. The cytotrophoblastic shell and complications of pregnancy. Placenta. 2017;60:134-39.
2. Burton GJ, Watson AL, Hempstock J, Skepper JN, Jauniaux E. Uterine glands provide histiotrophic nutrition for the human fetus during the first trimester of pregnancy. J Clin Endocrinol Metab. 2002;87:2954-59.
3. Hempstock J, Cindrova-Davies T, Jauniaux E, Burton GJ. Endometrial glands as a source of nutrients, growth factors and cytokines during the first trimester of human pregnancy; a morphological and immunohistochemical study. Reproductive Biology and Endocrinology. 2004;2:58.
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6. Turco MY, Gardner L, Hughes J, et al. Long-term, hormone-responsive organoid cultures of human endometrium in a chemically defined medium. Nat Cell Biol. 2017;19:568-77.
7. Boretto M, Cox B, Noben M, et al. Development of organoids from mouse and human endometrium showing endometrial epithelium physiology and long-term expandability. Development. 2017;144:1775-86.