Survival of human ovarian follicles from fetal to adult life: Apoptosis, apoptosis-related proteins, and transcription factor GATA-4

The majority of oocytes present in fetal ovaries are depleted before birth, and only about 400 will ovulate during the normal fertile life span. Studi es on animals have shown that apoptosis is the mechanism behind oocyte depl etion and follicular atresia. In the present study, we investigated the ext ent and localization of apoptosis in human fetal (aged 13-40 weeks) and adu lt ovaries. Furthermore, the expression of apoptosis-regulating proteins, b cl-2 and bax, and the relationship of transcription factor GATA-4 were stud ied. Apoptosis was found in ovarian follicles throughout fetal and adult li fe. During fetal development, apoptosis was localized mainly to primary ooc ytes and was highest between weeks 14-28, decreasing thereafter toward term . Expression of bcl-2 was observed only in the youngest fetal ovaries (week s 13-14), and bax was present in the ovaries throughout the entire fetal pe riod. In adult ovaries, apoptosis was detected in granulosa cells of second ary and antral follicles, and Bcl-2 and bax were expressed from primary fol licles onwards. During fetal ovarian development, GATA-4 messenger RNA and protein were localized to the granulosa cells, with expression being highes t in the youngest ovaries and decreasing somewhat toward term. The expressi on pattern of GATA-4 suggests that it may be involved in the mechanisms pro tecting granulosa cells from apoptosis from fetal to adult life. The result s indicate that depletion of ovarian follicles in the human fetus occurs th rough intrinsic mechanisms of apoptosis in oocytes, and later in adult life the survival of growing follicles may be primarily determined by granulosa cell apoptosis.