Endocrine Regulation in Preeclampsia Pathogenesis

Preeclampsia is a hypertensive disorder of pregnancy arising from aberrant placental development and dysregulated endocrine communication between maternal, placental and fetal compartments. Under normal conditions, oestrogens, progesterone and androgens coordinate trophoblast invasion, spiral artery remodelling and maternal vascular adaptation to meet foetal demands. Key enzymes such as aromatase and catechol-O-methyltransferase (COMT) govern local production of active steroids, while receptor systems—including nuclear estrogen receptors (ERα/ERβ), progesterone receptor (PR), androgen receptor (AR) and membrane-initiated G protein-coupled oestrogen receptor—translate hormonal cues into gene programmes controlling angiogenesis, inflammation and vasomotor tone. Impaired conversion of androgens to oestrogens, shifts in receptor expression or failure of non-genomic signalling can precipitate shallow trophoblast invasion and incomplete arterial conversion. The resulting placental hypoxia and release of anti-angiogenic factors induce maternal endothelial dysfunction, manifesting clinically as hypertension and multi-organ involvement. Elucidation of these endocrine pathways highlights opportunities for biomarker discovery and targeted interventions to reduce global maternal and perinatal morbidity.

Research from Nature Portfolio

Recent studies have demonstrated that activation of a membrane-bound oestrogen receptor in trophoblast cells stimulates Yes-associated protein (YAP) signalling, leading to increased expression of angiopoietin-like 4 (ANGPTL4) and enhanced cell invasion. Placental specimens from affected pregnancies display coordinated downregulation of this receptor, YAP and ANGPTL4, linking disruption of rapid oestrogen signalling to defective uteroplacental remodelling. In parallel, work on catechol-O-methyltransferase has revealed that its suppression during pregnancy undermines the generation of 2-methoxyestradiol, exacerbating maternal metabolic and vascular dysregulation. Restoration of 2-methoxyestradiol levels rescues maternal tolerance and attenuates adverse vascular responses, underscoring the importance of O-methylated oestrogen metabolites in maintaining cardiovascular adaptation in gestation.

Endocrine Regulation in Preeclampsia Pathogenesis publication trend

The graph below shows the total number of articles in endocrine regulation in preeclampsia pathogenesis across all publications each year (not limited to Nature Index journals).

Technical terms

Spiral artery remodelling: Transformation of maternal uterine arteries by invasive trophoblast cells to establish high-capacity blood flow to the placenta.

Trophoblast invasion: Migration of specialised placental cells into the maternal decidua to secure maternal–foetal exchange.

G protein-coupled oestrogen receptor (GPER): Membrane receptor that mediates rapid, non-genomic oestrogen signalling in trophoblast and vascular cells.

Angiopoietin-like 4 (ANGPTL4): Secreted glycoprotein regulating vascular permeability and cell invasiveness during placental development.

Catechol-O-methyltransferase (COMT): Enzyme that converts catechol oestrogens into methoxy derivatives, including 2-methoxyestradiol.

2-Methoxyestradiol (2-ME): Endogenous oestrogen metabolite with vasodilatory, anti-inflammatory and angiogenic properties.

Aromatase: Cytochrome P450 enzyme catalysing the conversion of androgens to oestrogens within the placenta.

Androgen receptor (AR): Nuclear receptor that binds testosterone and dihydrotestosterone to regulate gene transcription critical for vascular and placental function.

References

1. Sex Steroids Modulate Uterine-Placental Vasculature: Implications for Obstetrics and Neonatal Outcomes. Frontiers in Physiology (2016).
2. Revisiting Steroidogenic Pathways in the Human Placenta and Primary Human Trophoblast Cells. International Journal of Molecular Sciences (2021).
3. G protein-coupled estrogen receptor stimulates human trophoblast cell invasion via YAP-mediated ANGPTL4 expression. Communications Biology (2021).
4. Deficiency in catechol-o-methyltransferase is linked to a disruption of glucose homeostasis in mice. Scientific Reports (2017).
5. Connecting G protein-coupled estrogen receptor biomolecular mechanisms with the pathophysiology of preeclampsia: a review. Reproductive Biology and Endocrinology (2023).
6. Levels of sex steroid hormones and their receptors in women with preeclampsia. Reproductive Biology and Endocrinology (2020).
7. Androgens in maternal vascular and placental function: implications for preeclampsia pathogenesis. Reproduction (2018).