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Original Articles |
Department of Obstetrics and Gynecology (T.E.V., J.S.T.) and Department of Pathology (T.E.V., F.S., R.H., J.S.T.), University of Oulu, FIN-90220 Oulu, Finland; Children’s Hospital and Program for Developmental and reproductive Physiology, Biomedicum (M.A., M.H.), University of Helsinki, FIN-00290 Helsinki, Finland; Department of Physiology (H.B.), S-41345 Gothenburg University, Gothenburg, Sweden; Department of Endocrinology and Fertility, Division of Obstetrics and Gynecology (M.D., E.R.t.V.), University Hospital 3015 Utrecht, The Netherlands; Department of Pediatrics (M.H.), Washington University in St. Louis, St. Louis, Missouri 63110
Address all correspondence and requests for reprints to: Juha S. Tapanainen, M.D., Ph.D., Clinic of Obstetrics and Gynecology, University of Oulu, 90220 Oulu, Finland. E-mail: juha.tapanainen{at}oulu.fi
Abstract
The majority of oocytes present in fetal ovaries are depleted before birth, and only about 400 will ovulate during the normal fertile life span. Studies on animals have shown that apoptosis is the mechanism behind oocyte depletion and follicular atresia. In the present study, we investigated the extent and localization of apoptosis in human fetal (aged 13–40 weeks) and adult ovaries. Furthermore, the expression of apoptosis-regulating proteins, bcl-2 and bax, and the relationship of transcription factor GATA-4 were studied. Apoptosis was found in ovarian follicles throughout fetal and adult life. During fetal development, apoptosis was localized mainly to primary oocytes and was highest between weeks 14–28, decreasing thereafter toward term. Expression of bcl-2 was observed only in the youngest fetal ovaries (weeks 13–14), and bax was present in the ovaries throughout the entire fetal period. In adult ovaries, apoptosis was detected in granulosa cells of secondary and antral follicles, and Bcl-2 and bax were expressed from primary follicles onwards. During fetal ovarian development, GATA-4 messenger RNA and protein were localized to the granulosa cells, with expression being highest in the youngest ovaries and decreasing somewhat toward term. The expression pattern of GATA-4 suggests that it may be involved in the mechanisms protecting granulosa cells from apoptosis from fetal to adult life. The results indicate that depletion of ovarian follicles in the human fetus occurs through intrinsic mechanisms of apoptosis in oocytes, and later in adult life the survival of growing follicles may be primarily determined by granulosa cell apoptosis.
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