The importance of ERβ signalling in the ovary

Abstract

This review examines the evidence for a central role of oestrogen receptor b (ERb or ESR2 as listed in the MGI Database) in folliculogenesis and hence reproductive biology. Knockout mouse models have been a valuable resource in this respect. The ERb-null mouse exhibits a granulosa cell phenotype associated with the partial arrest of folliculogenesis and ovulatory dysfunction. Phyto-oestrogens such as genistein, which preferentially activate ERb, have been shown to alleviate the ovarian phenotype of the oestrogendepleted aromatase knockout mouse. In normal adult mice, genistein has been shown to cause reproductive defectives following neonatal administration. Studies of ovarian cancer have also informed the literature. A decline in ERb levels in epithelial ovarian cancers has been hypothesised to be associated with severity of disease and prognosis. Whereas the abundant expression of ERb in granulosa cell tumours (GCT) of the ovary and evidence that ERb signalling is transrepressed by the nuclear factor-kB pathway in GCT cell lines suggest a pathogenetic role for ERb in GCT. In recent years, studies into the impact of environmental oestrogens (either in the form of pesticides or plastics) on reproductive function have shown that ERb-selective toxins cause reproductive dysfunction and impair fertility. It remains to be established as to what genes are regulated by ERb in the ovary. Finally, ERb has been shown to be regulated by gonadotrophins, the pituitary hormones mediating ovarian function.

Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development

“…An interesting finding in this respect is the fact that nonclassical estrogen signaling has been shown previously to interact with the MAPK pathway 31 -a signaling pathway involved in the earliest stages of gonadal developmentalthough the operating mechanisms are different in humans and mice. In humans, MAPK signaling is essential for tilting the gene expression balance towards SOX9 expression; gain- of-function mutations of MAP3K1 lead to higher phosphorylation of downstream targets, causing decreased expression of SOX9 and increased expression of female-specific genes like β-catenin.…”

“…In humans, MAPK signaling is essential for tilting the gene expression balance towards SOX9 expression; gain- of-function mutations of MAP3K1 lead to higher phosphorylation of downstream targets, causing decreased expression of SOX9 and increased expression of female-specific genes like β-catenin. 2,31,32 In mice, the Mapk pathway acts through direct upregulation of Sry; homozygous loss-of-function variants of Map3k4 are reflected in a male-to-female sex reversal phenotype. 3,33 Nuclear receptor family members, to which the ERs belong, are known to exert their functions through different action mechanisms.…”

Targeting estrogen receptor subtypes (ERα and ERβ) with selective ER modulators in ovarian cancer

“…Furthermore, gene silencing with siRNAs for individual receptor subtypes confirmed that these effects were mediated via the respective receptors, without significant cross-reaction with the other subtype. The molecular pathways involved in the activation of ERa are well reported but the pathways involved in ERb activation are much less well established (Drummond & Fuller 2010). Therefore in this study, we also attempted to elucidate the molecular pathways involved.…”

Effects of Endocrine-disrupting Chemicals on Female Reproductive Health

“…ESR1 is expressed primarily in theca cells, and ESR2 is expressed in granulosa cells and essential for FSH-directed granulosa cell differentiation as well as for LH responsiveness [90,91]. ESR2 also facilitates mechanisms that promote follicle maturation from the early antral to the preovulatory stages [92,93]. In addition it may play a major role in primordial follicle formation in the ovary [93 -97].…”