Crosstalk between androgen and epidermal growth factor signalling in the ovary

Abstract

The development and survival of preantral follicles within the mammalian ovary must be tightly regulated in order to ensure a healthy supply of oocytes for the entirety of a woman’s reproductive lifespan. A complex regulatory network of both stimulatory and inhibitory factors exists to control activation of primordial follicles and preantral follicle growth. This thesis aimed to investigate interactions between local intraovarian growth factor and steroid signalling pathways. The epidermal growth factor (EGF) family, previously known to be essential during ovulation, was shown to play a role earlier during preantral follicle development. ErbB receptor subtypes EGFR and ErbB2 as well as EGF-like ligands were expressed in isolated mouse preantral follicles. Cultured preantral follicles exposed to exogenous EGF ligand grew significantly larger than controls and displayed widespread alterations in the expression of genes and proteins essential to follicular development. Receptor inhibitor studies showed that EGF signalling between and within preantral follicles likely activates both EGFR homodimers and EGFR-ErbB2 heterodimers that converge on the MAPK cascade. Androgens were also shown to stimulate preantral follicle growth and alter expression of proteins key to follicular development in culture. Androgens signal primarily through the androgen receptor (AR) that acts classically as a ligand activated transcription factor, however it was shown that AR can also induce rapid non-genomic phosphorylation events in the MAPK cascade in mouse granulosa cells. Interactions between androgen and EGF signalling were uncovered in preantral follicles. Androgens regulate expression of ErbB receptors and EGF-like ligands in cultured preantral follicles. Interestingly, selective inhibition of either EGFR or ErbB2 attenuated the effect of androgens on follicle growth, indicating that ErbB activity is required for maximal androgenic stimulation. The mechanisms of androgen-EGF crosstalk remain unclear, however this novel interaction provides insights into the complex and interconnected regulatory networks within the ovary that control preantral follicle development.