Acquisition of gonadotropin dependence by early antral follicles and the challenges to promote their growth in vitro

Abstract This review aims to discuss the main factors involved in the development of early antral follicles until gonadotropin dependence. This follicular phase is characterized by intense proliferation of granulosa cells, formation of a fluid-filled cavity, morphological differentiation of cumulus cells, mural granulosa cells and recruitment of theca cells. The interaction between oocyte, granulosa and theca cells is crucial for follicular growth and hormone production. Growth factors produced by the oocyte, such as growth and differentiation factor-9 (GDF-9) and bone morphogenetic protein-15 (BMP-15), regulate granulosa cell proliferation and differentiation and antral cavity development, as well as stimulate the production of follicle-stimulating hormone (FSH) receptors in granulosa cells. In response to FSH, granulosa cells secrete C-type natriuretic peptide (CNP), which acts through its receptor to increase cyclic guanosine monophosphate (cGMP) production and consequently follicular development. Granulosa cells also produce insulin-like growth factor-1 (IGF-1) and increase aromatase enzyme activity, which results in greater sensitivity to gonadotropins and follicular steroidogenesis. The absence of IGF-1 signaling causes cessation of follicular growth at the early antral stage. Many other local factors are involved in the regulation of follicular development. Therefore, this review brings relevant data for a better understanding of the mechanisms involved in the control of early antral follicle growth, emphasizing the role of endocrine and paracrine factors, the oocyte-granulosa cell interaction and the processes of follicular atresia. The challenges for the establishment of efficient culture systems for in vitro growth of early antral follicles are also discussed. Resumo Esta revisão tem como objetivo discutir os principais fatores envolvidos no desenvolvimento de folículos antrais iniciais até a dependência de gonadotrofinas. Essa fase folicular é caracterizada por intensa proliferação de células da granulosa, formação de uma cavidade preenchida por líquido, diferenciação morfológica das células do cumulus, células da granulosa murais e recrutamento de células da teca. A interação entre oócito, células da granulosa e da teca é determinante para o crescimento folicular e produção hormonal. Fatores de crescimento produzidos pelo oócito, fator de crescimento e diferenciação-9 (GDF-9) e proteína morfogenética óssea-15 (BMP-15), regulam a proliferação e