Ovulation and adequate follicle growth require follicle-stimulating hormone (FSH) and insulin-like growth factors (IGFs). Animal studies and findings in human granulosa cells (GCs) have demonstrated that FSH fails to stimulate follicular growth in the absence of IGF1 receptor (IGF1R) activity. Understanding the interaction between FSH and IGF actions during follicular development may lead to advances in infertility treatments by exploiting the mechanisms that coordinate these signals. We demonstrated that in human, mouse, and rat GCs the well- known stimulatory effect of FSH on AKT activation and on preantral to preovulatory differentiation depends on the expression and activation of the IGF1R. The objective of this project is to identify the crosstalk between FSH and IGF receptor signaling in ovarian GCs. Our central hypothesis is that FSH inhibits pathways that negatively regulate IGF1R, IRS1/2, and/or PI3K activity, facilitating full activation of AKT by locally produced IGFs. In humans, we extend this hypothesis by suggesting that FSH increases IGF1R activity also by stimulating IGF2 gene expression. To test our central hypothesis, we will pursue three specific aims: 1. Identify the crosstalk mechanism between FSHR and IGF1R signaling in GCs. Primary preantral GCs will be used to systematically examine FSH and IGF signaling crosstalk. 2. Elucidate IGF1R-dependent mechanisms involved in follicle growth and maturation. We will test our central hypothesis using GC-specific IGF1R knockout mice, which display fertility defects. 3. Characterize FSH and IGF2 interaction and IGF2 regulation in human GCs.
This aim will test the hypothesis that FSH enhances IGF2 expression and IGF1R signaling, both of which are needed for the activation of the differentiation program in human GCs. The proposed research will significantly contribute to our understanding of the mechanisms by which FSH and IGFs interact. This information will be useful in the planning of new interventions for controlling or optimizing follicle maturation. This research could also serve as a foundation for perfecting diagnosis and treatment of ovulatory defects, to improve in vitro fertilization, or to develop new contraceptive approaches.
This project is relevant to public health because fully understanding the mechanisms involved in the formation of preovulatory follicles will provide the foundation for perfecting the diagnosis and treatment of ovulatory defects and for improving IVF outcomes. This project will generate knowledge that could help reduce the burden of infertility treatments.
| Bennett-Toomey, Jill; Stocco, Carlos (2018) GATA Regulation and Function During the Ovarian Life Cycle. Vitam Horm 107:193-225 |
| Stocco, Carlos; Baumgarten, Sarah C; Armouti, Marah et al. (2017) Genome-wide interactions between FSH and insulin-like growth factors in the regulation of human granulosa cell differentiation. Hum Reprod 32:905-914 |
| Baumgarten, Sarah C; Armouti, Marah; Ko, CheMyong et al. (2017) IGF1R Expression in Ovarian Granulosa Cells Is Essential for Steroidogenesis, Follicle Survival, and Fertility in Female Mice. Endocrinology 158:2309-2318 |
| Convissar, Scott; Armouti, Marah; Fierro, Michelle A et al. (2017) Regulation of AMH by oocyte-specific growth factors in human primary cumulus cells. Reproduction 154:745-753 |
| Stocco, Carlos (2016) Follicle-stimulating Hormone (FSH) Phosphorylation of Protein Kinase B (AKT) Remains Controversial. J Biol Chem 291:14385 |
