Skip to main content Accessibility help

How Can Female Germline Stem Cells Contribute to the Physiological Neo-Oogenesis in Mammals and Why Menopause Occurs?

  • Antonin Bukovsky (a1)


At the beginning of the last century, reproductive biologists have discussed whether in mammalian species the fetal oocytes persist or are replaced by neo-oogenesis during adulthood. Currently the prevailing view is that neo-oogenesis is functional in lower vertebrates but not in mammalian species. However, contrary to the evolutionary rules, this suggests that females of lower vertebrates have a better opportunity to provide healthy offspring compared to mammals with oocytes subjected to environmental threats for up to several decades. During the last 15 years, a new effort has been made to determine whether the oocyte pool in adult mammals is renewed as well. Most recently, Ji Wu and colleagues reported a production of offspring from female germline stem cells derived from neonatal and adult mouse ovaries. This indicates that both neonatal and adult mouse ovaries carry stem cells capable of producing functional oocytes. However, it is unclear whether neo-oogenesis from ovarian somatic stem cells is physiologically involved in follicular renewal and why menopause occurs. Here we review observations that indicate an involvement of immunoregulation in physiological neo-oogenesis and follicular renewal from ovarian stem cells during the prime reproductive period and propose why menopause occurs in spite of persisting ovarian stem cells.


Corresponding author


Hide All
Allen, E. (1923). Ovogenesis during sexual maturity. Am J Anat 31, 439481.
Allen, E. & Creadick, R.N. (1937). Ovogenesis during sexual maturity, the first stage, mitosis in the germinal epithelium, as shown by the colchicine technique. Anat Rec 69, 191195.
Allen, E., Kountz, W.B. & Francis, B.F. (1925). Selective elimination of ova in the adult ovary. Am J Anat 34, 445467.
Block, E. (1952). Quantitative morphological investigations of the follicular system in women. Variations at different ages. Acta Anat (Basel) 14, 108123.
Bousfield, G.R., Butnev, V.Y., Gotschall, R.R., Baker, V.L. & Moore, W.T. (1996). Structural features of mammalian gonadotropins. Mol Cell Endocrinol 125, 319.
Bukovsky, A. (2006a). Immune system involvement in the regulation of ovarian function and augmentation of cancer. Microsc Res Tech 69, 482500.
Bukovsky, A. (2006b). Oogenesis from human somatic stem cells and a role of immune adaptation in premature ovarian failure. Curr Stem Cell Res Ther 1, 289303.
Bukovsky, A. (2007a). Cell commitment by asymmetric division and immune system involvement. Prog Mol Subcell Biol 45, 179204.
Bukovsky, A. (2007b). Human oogenesis and follicular renewal from ovarian somatic stem cells. In Stem Cell Research Developments, Fong, C.A. (Ed.), pp. 229272. Hauppauge, NY: Nova Science Publishers, Inc.
Bukovsky, A. (2008). Ovarian stem cells and mammalian neo-oogenesis. Microsc Microanal 14(S2), 1474CD1475CD.
Bukovsky, A. (2009). Sex steroid-mediated reprogramming of vascular smooth muscle cells to stem cells and neurons: Possible utilization of sex steroid combinations for regenerative treatment without utilization of in vitro developed stem cells. Cell Cycle 8(24), 40794084.
Bukovsky, A., Ayala, M.E., Dominguez, R., Svetlikova, M. & Selleck-White, R. (2007). Bone marrow derived cells and alternative pathways of oogenesis in adult rodents. Cell Cycle 6(18), 23062309.
Bukovsky, A. & Caudle, M.R. (2008). Immune physiology of the mammalian ovary—A review. Am J Reprod Immunol 59, 1226.
Bukovsky, A., Caudle, M.R., Gupta, S.K., Svetlikova, M., Selleck-White, R., Ayala, M.E. & Dominguez, R. (2008a). Mammalian neo-oogenesis and expression of meiosis-specific protein SCP3 in adult human and monkey ovaries. Cell Cycle 7(5), 683686.
Bukovsky, A., Caudle, M.R. & Svetlikova, M. (2008b). Steroid-mediated differentiation of neural/neuronal cells from epithelial ovarian precursors in vitro. Cell Cycle 7(22), 35773583.
Bukovsky, A., Caudle, M.R., Svetlikova, M. & Upadhyaya, N.B. (2004). Origin of germ cells and formation of new primary follicles in adult human ovaries. Reprod Biol Endocrinol 2, 20; available at
Bukovsky, A., Caudle, M.R., Svetlikova, M., Wimalasena, J., Ayala, M.E. & Dominguez, R. (2005a). Oogenesis in adult mammals, including humans: A review. Endocrine 26, 301316.
Bukovsky, A., Caudle, M.R., Virant-Klun, I., Gupta, S.K., Dominguez, R., Svetlikova, M. & Xu, F. (2009). Immune physiology and oogenesis in fetal and adult humans, ovarian infertility, and totipotency of adult ovarian stem cells. Birth Defects Res C Embryo Today 87, 6489.
Bukovsky, A., Gupta, S.K., Bansal, P., Chakravarthy, S., Chaudhary, M., Svetlikova, M., White, R.S., Copas, P., Upadhyaya, N.B., Van Meter, S.E. & Caudle, M.R. (2008c). Production of monoclonal antibodies against recombinant human zona pellucida glycoproteins: Utility in immunolocalization of respective zona proteins in ovarian follicles. J Reprod Immunol 78(2), 102114.
Bukovsky, A., Gupta, S.K., Svetlikova, M., White, R.S., Copas, P., Upadhyaya, N.B. & Van Meter, S.E. (2008d). Immunoregulation of ovarian homeostasis. In Novel Concepts in Ovarian Endocrinology, Gonzalez-Bulnes, A. (Ed.), pp. 131168. Kerala, India: Research Signpost.
Bukovsky, A., Keenan, J.A., Caudle, M.R., Wimalasena, J., Upadhyaya, N.B. & Van Meter, S.E. (1995). Immunohistochemical studies of the adult human ovary: Possible contribution of immune and epithelial factors to folliculogenesis. Am J Reprod Immunol 33, 323340.
Bukovsky, A., Svetlikova, M. & Caudle, M.R. (2005b). Oogenesis in cultures derived from adult human ovaries. Reprod Biol Endocrinol 3, 17; available at
Bukovsky, A. & Virant-Klun, I. (2006). Adult stem cells in the human ovary. In Stem Cells in Reproductive Medicine: Basic Science & Therapeutic Potential, Simon, C. & Pellicer, A. (Eds.), pp. 5369. London: Informa Healthcare.
Bukovsky, A., Virant-Klun, I., Svetlikova, M. & Willson, I. (2006). Ovarian germ cells. Methods Enzymol 419, 208258.
Eggan, K., Jurga, S., Gosden, R., Min, I.M. & Wagers, A.J. (2006). Ovulated oocytes in adult mice derive from non-circulating germ cells. Nature 441, 11091114.
Erickson, B.H. (1966). Development and senescence of the postnatal bovine ovary. J Anim Sci 25, 800805.
Evans, H.M. & Swezy, O. (1931). Ovogenesis and the normal follicular cycle in adult mammalia. Mem Univ Calif 9, 119224.
Franchi, L.L., Mandl, A.M. & Zuckerman, S. (1962). The development of the ovary and the process of oogenesis. In The Ovary, Zuckerman, S. (Ed.), pp. 188. London: Academic Press.
Ganguly, A., Bukovsky, A., Sharma, R.K., Pankaj, B., Bhandari, B. & Gupta, S.K. (2010). In humans, zona pellucida glycopotein-1 binds to spermatozoa and induces acrosomal exocytosis. Hum Reprod 25, 16431656.
Hershkovitz, R., Erez, O., Sheiner, E., Landau, D., Mankuta, D. & Mazor, M. (2003). Elevated maternal mid-trimester chorionic gonadotropin > or =4 MoM is associated with fetal cerebral blood flow redistribution. Acta Obstet Gynecol Scand 82, 2227.
Ingram, D.L. (1962). Atresia. In The Ovary, Zuckerman, S. (Ed.), pp. 247273. London: Academic Press.
Johnson, J. (2006). Stem cell support of ovary function and fertility. In Stem Cells in Reproductive Medicine: Basic Science & Therapeutic Potential, Simon, C. & Pellicer, A. (Eds.), pp. 3144. London: Informa Healthcare.
Johnson, J., Bagley, J., Skaznik-Wikiel, M., Lee, H.J., Adams, G.B., Niikura, Y., Tschudy, K.S., Tilly, J.C., Cortes, M.L., Forkert, R., Spitzer, T., Iacomini, J., Scadden, D.T. & Tilly, J.L. (2005). Oocyte generation in adult mammalian ovaries by putative germ cells in bone marrow and peripheral blood. Cell 122, 303315.
Johnson, J., Canning, J., Kaneko, T., Pru, J.K. & Tilly, J.L. (2004). Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature 428, 145150.
Kerr, J.B., Duckett, R., Myers, M., Britt, K.L., Mladenovska, T. & Findlay, J.K. (2006). Quantification of healthy follicles in the neonatal and adult mouse ovary: Evidence for maintenance of primordial follicle supply. Reproduction 132, 95109.
Kingery, H.M. (1917). Oogenesis in the white mouse. J Morphol 30, 261315.
Lee, H.J., Selesniemi, K., Niikura, Y., Niikura, T., Klein, R., Dombkowski, D.M. & Tilly, J.L. (2007). Bone marrow transplantation generates immature oocytes and rescues long-term fertility in a preclinical mouse model of chemotherapy-induced premature ovarian failure. J Clin Oncol 25, 31983204.
Liu, Y., Wu, C., Lyu, Q., Yang, D., Albertini, D.F., Keefe, D.L. & Liu, L. (2007). Germline stem cells and neo-oogenesis in the adult human ovary. Dev Biol 306, 112120.
Mathe, G. (1997). Immunity aging. I. The chronic perduration of the thymus acute involution at puberty? Or the participation of the lymphoid organs and cells in fatal physiologic decline? Biomed Pharmacother 51, 4957.
Mossman, H.W. & Duke, K.L. (1973). Some comparative aspects of the mammalian ovary. In Handbook of Physiology, Sect. 7: Endocrinology, Greep, R.O. (Ed.), pp. 389402. Washington, DC: American Physiological Society.
Motta, P.M., Van Blerkom, J. & Makabe, S. (1980). Changes in the surface morphology of ovarian “germinal” epithelium during the reproductive cycle and in some pathological conditions. J Submicrosc Cytol 12, 407425.
Penny, R., Olambiwonnu, O. & Frasier, S.D. (1976). Measurement of human chorionic gonadotropin (HCG) concentrations in paired maternal and cord sera using an assay specific for the beta subunit of HCG. Pediatrics 58, 110114.
Romeu, M., Simon, C. & Pellicer, A. (2006). Adult stem cells in the human ovary: Hope or fiction? In Stem Cells in Reproductive Medicine: Basic Science & Therapeutic Potential, Simon, C. & Pellicer, A. (Eds.), pp. 4552. London: Informa Healthcare.
Tilly, J.L. & Telfer, E.E. (2009). Purification of germline stem cells from adult mammalian ovaries: A step closer towards control of the female biological clock? Mol Hum Reprod 15, 393398.
Tres, L.L. (2005). XY chromosomal bivalent: Nucleolar attraction. Mol Reprod Dev 72, 16.
Van Blerkom, J. & Motta, P.M. (1979). The Cellular Basis of Mammalian Reproduction. Baltimore-Munich: Urban & Schwarzenberg.
Virant-Klun, I., Rozman, P., Cvjeticanin, B., Vrtacnik-Bokal, E., Novakovic, S. & Ruelicke, T. (2009). Parthenogenetic embryo-like structures in the human ovarian surface epithelium cell culture in postmenopausal women with no naturally present follicles and oocytes. Stem Cells Dev 18(1), 137150.
Virant-Klun, I., Zech, N., Rozman, P., Vogler, A., Cvjeticanin, B., Klemenc, P., Malicev, E. & Meden-Vrtovec, H. (2008). Putative stem cells with an embryonic character isolated from the ovarian surface epithelium of women with no naturally present follicles and oocytes. Differentiation 76(8), 843856.
Waldeyer, W. (1870). Eierstock und Ei. Leipzig, Germany: Engelmann.
Zou, K., Yuan, Z., Yang, Z., Luo, H., Sun, K., Zhou, L., Xiang, J., Shi, L., Yu, Q., Zhang, Y., Hou, R. & Wu, J. (2009). Production of offspring from a germline stem cell line derived from neonatal ovaries. Nat Cell Biol 11, 631636.
Zuckerman, S. (1951). The number of oocytes in the mature ovary. Recent Prog Horm Res 6, 63109.


How Can Female Germline Stem Cells Contribute to the Physiological Neo-Oogenesis in Mammals and Why Menopause Occurs?

  • Antonin Bukovsky (a1)


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed