Oestrogen receptors and reproductive competence

Oestrogens are steroids that are made in the testes and ovaries of men and women. They not only regulate our fertility but also have a major impact on our cardiovascular system, our brain, our bones and our immune system. Our quest to understand how sex steroids alter cell function has focused upon investigating the expression and functional activity of binding proteins (receptors) that are found in reproductive organs and cancers. In collaboration with clinical colleagues we have used antibodies to map the pattern of expression of oestrogen receptors (ERa and ER_) in normal human tissues such as the testis, ovary and the endometrial lining of the womb and also in cancers of the breast, colon and endometrium. Our current studies are using a variety of cell culture based assays and fluorescent protein imaging, to work out what impact oestrogens have on immune cells, cancers and fertility. We will be considering both the behaviour of receptors following binding to steroids and also what happens when they are activated by signals induced by growth factors. We hope that the results obtained may assist us in developing new approaches to the treatment of infertility and pathologies of the reproductive system.

Oestrogens are synthesised within the gonads of adult men and pre-menopausal women. These steroids are essential regulators of fertility and also have an impact on the cardiovascular system, the immune system, the skeleton, the breast and the brain. Oestrogen action is mediated via specific nuclear receptors (ER). Two receptors known as oestrogen receptor alpha (ERalpha) and oestrogen receptor beta (ERbeta) are encoded by the ESR1 and ESR2 genes respectively. They belong to a superfamily of genes that includes three closely related orphan receptors know as oestrogen-related receptors alpha (ERRalpha), beta (ERRbeta) and gamma (ERRggamma). We have recently documented expression of ERRalpha and beta in human endometrium and obtained data suggesting that the long form of ERRbeta can modify ERalpha-dependent gene activation.|ERalpha and ERbeta act as ligand-activated transcription factors and can form homo- or heterodimers. ERs tagged with fluorescent proteins cloned into viral vectors are being used to investigate homo- and hetero-dimer formation in vitro using confocal imaging techniques (FRET, FRAP) and reporter assays with receptor subtype selective ligands (SERMS). We are also using cell-based approaches to investigate the impact of steroid ligand-independent pathways on receptor activity and gene expression. |In collaboration with Professory Hilary Critchely (University of Edinburgh) we have been studying the impact of oestrogens and androgens on cells within the human endometrium, a tissue that undergoes dynamic, cyclical remodelling in response to steroid hormones. The endometrium hosts a diverse group of immune cells including a phenotypically distinct population of natural killler [uNK] cells that that congregate at the maternal-fetal interface and play an essential role in establishment of pregnancy. We have discovered that these CD56+ cells express ERbeta but not ERalpha and Ilumina array analysis has revealed that transient exposure to oestradiol has a direct impact on their pattern of gene expression. |Our studies have shed new light on the role played by ERs and ERRs in the regulation of human fertility and in pathologies of the reproductive tract allowing the development of new treatment strategies.