Nuclear hormone receptors and female reproduction.

BACKGROUND: Nuclear Hormone Receptors (NHR) are, as the name implies, receptors located in the cell nucleus that have transcription modulating characteristics. Activated non-steroidal lipophilic ligands bind these receptors resulting in dimerisation of the ligands, DNA-binding and transcriptional regulation of target proteins that influence especially cell differentiation, metabolic homeostasis and embryogenesis. METHODS: This review is based on publications derived from PubMed based pursuit of scientific literature in conjunction with the authors' experience. RESULTS: Here, a summary of NHR family members (RXR, PPAR, VDR, TR) first in respect to known general aspects such as ligands, binding domains, signalling mechanism and second focussing especially their influence on female reproduction is offered. Furthermore, crosstalk with other prominent signalling proteins important to trophoblast function [signal transducer and activator of transcription (STAT), mitogen-activated protein kinase (MAPK), nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NFκB), Akt/ phosphaidyl-3-kinase (PI3K), and Wnt, are described. CONCLUSION: Considering their attributes, it is not surprising that NHR family members play a central role in female reproduction by targeting cell differentiation, metabolic homeostasis and embryogenesis. However, it seems that crosstalk depends on stage of trophoblast differentiation.

Retinoid X receptor α and retinoids are key regulators in apoptosis of trophoblasts of patients with recurrent miscarriages.

The retinoid X receptor α (RXRα) is a nuclear hormone receptor that is able to bind other nuclear receptors in a heterodimeric complex, thereby activating gene transcription. Recently, we identified enhanced expression of RXRα in extravillous trophoblasts (EVT) and villous trophoblasts (VT) of miscarried placentas. In addition, an increased number of apoptotic EVT was present in miscarried placentas. In this study, on the basis of immunocytochemical analysis, western blots, and quantitative real-time reverse transcription PCR, we could demonstrate a reduced expression of RXRα in choriocarcinoma cell lines and in human VTs after stimulation with the retinoids 9-cis-retinoic acid and all-trans-retinoic acid and the prostaglandin 15-deoxy-Δ(12,14)-prostaglandin J(2). Furthermore, a simultaneous expression of RXRα and the apoptotic marker M30 CytoDEATH in EVT of miscarried placentas from the first trimester was shown. In EVT of control placentas from legal termination of pregnancies, no co-expression of RXRα and M30 could be detected. A likely conclusion is that RXRα plays an important role in the induction of apoptosis. Downregulation of RXRα, as observed in the tested choriocarcinoma cells and trophoblasts, might serve as a protection against apoptosis and miscarriage. In conclusion, RXRα represents a potential target in the treatment of recurrent miscarriages.