Abstract
Estradiol (E2) is a major hormone controlling women fertility, in particular folliculogenesis. This steroid, which is locally produced by granulosa cells (GC) within ovarian follicles, controls the development and selection of dominant preovulatory follicles. E2 effects rely on a complex set of nuclear and extra-nuclear signal transduction pathways principally triggered by its nuclear receptors, ERα and ERβ. These transcription factors are differentially expressed within follicles, with ERβ being the predominant ER in GC. Several ERβ splice isoforms have been identified and display specific structural features, which greatly complicates the nature of ERβ-mediated E2 signaling. This review aims at providing a concise overview of the main actions of E2 during follicular growth, maturation, and selection in human. It also describes the current understanding of the various roles of ERβ splice isoforms, especially their influence on cell fate. We finally discuss how E2 signaling deregulation could participate in two ovarian pathogeneses characterized by either a follicular arrest, as in polycystic ovary syndrome, or an excess of GC survival and proliferation, leading to granulosa cell tumors. This review emphasizes the need for further research to better understand the molecular basis of E2 signaling throughout folliculogenesis and to improve the efficiency of ovarian-related disease therapies.
Highlights
Estradiol (E2) is a steroid hormone that regulates important events occurring during the normal menstrual cycle in women, especially the sequence of ovarian follicle growth and maturation
Based on the well-established importance of E2 in follicular development and maturation, the current review aims at highlighting the potential role of E2 signaling in two human ovarian pathologies that still need better treatment strategies, such as polycystic ovary syndrome (PCOS) and granulosa cell tumors (GCT)
Patients with a loss of function mutation in ESR2 have been recently described and associated with complete amenorrhea [74,75] or with 46 XY disorders of sex development [76]. All these findings indicate that the differential level of expression of each ERβ isoform may play important roles in E2 action and sensitivity, and they might be involved in various follicular deregulations leading to ovarian pathologies, such as polycystic ovary syndrome (PCOS) and granulosa cell tumor (GCT)
Summary
Estradiol (E2) is a steroid hormone that regulates important events occurring during the normal menstrual cycle in women, especially the sequence of ovarian follicle growth and maturation. E2 mediates its effects principally through the activation of ERα and ERβ receptors that are members of the superfamily of ligand-activated transcription factors [4] Both receptors act mainly in the nucleus to regulate gene transcription through direct (on putative estrogen response element sequences, ERE) or indirect (though tethering to other transcription factors) DNA interactions. This genomic signaling is further augmented by the non-genomic GPER1 ( known as GPR30 or GPER), which is a membrane-bound G-protein-coupled receptor capable of mediating both rapid and transcriptional events in response to high levels of E2 [5]. This review gives a special emphasis to the recent advances in the biology of ERβ signaling and to the possible contribution of its different isoforms in those pathologies
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