Estradiol Signaling at the Heart of Folliculogenesis: Its Potential Deregulation in Human Ovarian Pathologies

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.

cAMP-Dependent Signaling and Ovarian Cancer

“…The two pituitary gonadotropins, FSH and LH, manifest their functions during all stages of the menstrual cycle, starting from follicle recruitment, through their growth and maturation, to ovulation of the Graafian follicle [ 71 ]. Folliculogenesis begins in fetal life and depends on the interaction of many genes and complex machinery of coordinated expression processes [ 72 , 73 ]. FSH and LH by binding to their membrane receptors activate intracellular signaling cascades, the action of which is adapted to the stage and context, and the intended direction is the development of the ovarian follicles [ 74 ].…”

Chlorogenic Acid Restores Ovarian Functions in Mice with Letrozole-Induced Polycystic Ovarian Syndrome Via Modulation of Adiponectin Receptor

“…Here, it was observed that PCOS mice had decreased concentrations of Ar and Esr1 mRNA levels, but in our research, CGA therapy reversed this downregulation in mice with PCOS. Ar and Esr1 transcripts have been shown to serve a function of proliferation in follicular growth [ 44 , 45 ], and elevated Ar levels can facilitate granulosa cell proliferation and differentiation [ 46 ]. Fshr moderately controls follicle growth during the baseline follicle growth phase by working in synergy with other stimulating substances, such as androgens [ 47 ].…”

Effect of the ratios of estradiol increase on the outcome of in vitro fertilization-embryo transfer with antagonist regimens: a single center retrospective cohort study

“…At this point, estrogen growth may be linked to recruited follicles. As the follicle grows, follicular granulosa cells increase in number and exhibit aromatase activity [ 35 ]. Therefore, follicular fluid contains high levels of estrogen.…”