Skip to main content
SpringerLink
Log in

Polycystic ovary syndrome — loss of the apoptotic mechanism in the ovarian follicles?

  • Views on Pathogenetic Mechanisms
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Polycystic ovary syndrome (PCOS) is the most prevalent female endocrinopathy and the largest single cause of anovulatory infertility. The PCOS is characterized by multiple small antral follicles arrested in their development but nonatretic and viable. The hyperexpression of some growth factors (e.g. EGF/TGF alpha) in PCOS, considered to be survival or antiapoptotic factors, led to the hypothesis of their involvement in the blocking of apoptosis and atresia leading to an accumulation of multiple small antral follicles. Diminished FSH stimulation and accumulation of androgens could explain the arrest of progress to the preovulatory stage. Further investigation of the pathogenesis of PCOS is needed on the modulation of tumour suppressor and apoptosis genes such as p53, BAX or the APO/FAS system and the over expression of survival genes such as BCL2.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Hughes F.M., Gorospe W.C. Biochemical indentification of apoptosis (programmed cell death) in granulosa cells: evidence for a potential mechanism underlying follicular atresia. Endocrinol. 129: 2415, 1991.

    Article  CAS  Google Scholar 

  2. Tilly J.L. Ovarian follicular atresia: a model to study the mechanism of physiological cell death. Endocr. J. 1: 67, 1993.

    Google Scholar 

  3. Hsueh A.J.W., Billig H., Tsafriri A. Ovarian follicle atresia: a hormonally controlled apoptotic process. Endocr. Rev. 15: 707, 1994.

    PubMed  CAS  Google Scholar 

  4. Tilly J.L. Apoptosis and ovarian function. Rev. Reprod. 1: 162, 1996.

    Article  PubMed  CAS  Google Scholar 

  5. Amsterdam A., Selvaraj N. Control of differentiation, transformation and apoptosis in granulosa cells by oncogenes, oncoviruses and tumor suppressor genes. Endocr. Rev. 18: 435, 1997.

    PubMed  CAS  Google Scholar 

  6. Gibori G., Khan I., Warshaw M.L. et al. Placental derived regulators and the complex control of luteal cell function. Recent Prog. Horm. Res. 44: 377, 1988.

    PubMed  CAS  Google Scholar 

  7. Juengel J.L., Garverick H.A., Johnson A.L. et al. Apoptosis during luteal regression in cattle. Endocrinology 132: 249, 1993.

    PubMed  CAS  Google Scholar 

  8. Zheng J., Fricke P.M., Reynolds L.P., Redmer D.A. Evaluation of growth, cell proliferation and cell death in bovine corpora lutea throughout the estrus cycle. Biol. Reprod. 51: 623, 1994.

    Article  PubMed  CAS  Google Scholar 

  9. Jo T., Tomiyama T., Ohashi K. et al. Apoptosis of cultured mouse luteal cells induced by tumor necrosis factor-alpha and interferon gamma. Anat. Rec. 241: 70, 1995.

    Article  PubMed  CAS  Google Scholar 

  10. Fraser H.M., Lunn S.F., Cowen G.M., Illingworth P.J. Induced luteal regression in the primate: evidence for apoptosis and changes in c-myc protein. J. Endocrinol. 147: 131, 1995.

    Article  PubMed  CAS  Google Scholar 

  11. Pitzer F., Dantes A., Fuchs T. et al. Removal of proteasomes from the nucleus and their accumulation in apoptotic blebs during programmed cell death. FEBS Lett. 394: 46, 1996.

    Article  Google Scholar 

  12. Amsterdam A., Breckwoldt M., Dantes A. et al. Ultrastructural aspects of cAMP and p53-mediated apoptosis in normal and ras- transformed granulosa cells. In: Tilly J.L., Strauss III J.F., Tenniswood M. (Eds.), Serono Symposium on Cell Death in Reproductive Physiology. Springer, New York, 1997.

    Google Scholar 

  13. Tilley J.L., Tilly K.I., Perez G.I. The genes of cell death cellular susceptibility to apoptosis in the ovary: a hypothesis. Cell Death Diff. 4: 180, 1997.

    Article  Google Scholar 

  14. Amersterdam A., Keren-Tal I., Aharoni D., Dantes A. Control of differentiation and programmed cell death by cAMP and p53-generated signals in ras-transformed cells. In: Waxman A. (Ed.), Challenges of Modern Medicine, Vol 10, Differentiation Therapy. Ares-Serono Publications, Rome, 1996, p. 83.

    Google Scholar 

  15. Amsterdam A., Aharoni A., Dantes A. et al. Involvement of protooncogenes, oncogenes and oncoviruses in granulosa cell steroidogenesis, carcinogenesis and programmed cell death. In: Fujimoto S., Hsueh J.F., Strauss II T., Tanaka T. (Eds.), New Achievements in Research of Ovarian Function. Ares-Serono, Rome, 1995, p. 315.

    Google Scholar 

  16. Amsterdam A., Keren-Tal I., Aharoni D. p53 and cAMP in differentiation and apoptosis in steroidogenic cells. Steroids 61: 252, 1996.

    Article  PubMed  CAS  Google Scholar 

  17. Amsterdam A., Dantes A., Selvaraj N., Aharoni D. Apoptosis in steroidogenic cells: struture-function analysis. Steroids 62: 207, 1997.

    Article  PubMed  CAS  Google Scholar 

  18. De Felici M. Ovarian follicular atresia: a model for apoptosis. Cell Death Differ. 4: 260, 1997.

    Article  PubMed  CAS  Google Scholar 

  19. Tilly K.I., Banerjee S., Banerjee P.P., Tilly J.L. Expression of the p-53 and Wilmis tumor suppressor genes in the rat ovary: gonadotropin repression in vivo and immunohistochemical localization of p53 protein to apoptotic granulosa cells of atretic follicles. Endocrinology 136: 1394, 1995.

    PubMed  CAS  Google Scholar 

  20. Keren-Tal I., Suh B.S., Dantes A. et al. Involvement of p53 expression in cAMP mediated apoptosis in immortalized granulosa cells. Exp. Cell Res. 218: 283, 1995.

    Article  PubMed  CAS  Google Scholar 

  21. Tilly J.L., Tilly K.I., Kenton L.M., Johnson A.L. Expression of members of the Bcl-2 gene family in the immature rat ovary: equine chorionic gonadotropin mediated inhibition of granulosa cell apoptosis is associated with decreased Bax and constitutive Bcl-2 and Bcl-x long messenger ribonucleic acid levels. Endocrinology 136: 232, 1995.

    PubMed  CAS  Google Scholar 

  22. Shaulian E., Resnitzky D., Shifman O. et al. Enhancement of cell survival by bFGF correlates with increased Mdm2 oncoprotein levels. Oncogene 15: 2717, 1997.

    Article  PubMed  CAS  Google Scholar 

  23. Aharoni D., Dantes A., Oren M., Amsterdam A. c-AMP mediated signals as determinants for apoptosis in primary granulosa cells. Exp. Cell Res. 218: 271, 1995.

    Article  PubMed  CAS  Google Scholar 

  24. Hosokawa K., Dantes A., Schere-Levy C. et al. Modulation of MDM2 expression and p53-induced apoptosis in immortalized human ovarian granulosa cells. In press.

  25. Franks S., Gharani N., Waterworth D. et al. The genetic basis of polycystic ovary syndrome. Hum. Reprod. 12: 2641, 1997.

    Article  PubMed  CAS  Google Scholar 

  26. Adams J., Franks S., Poison D.W. et al. Multifollicular ovaries: clinical and endocrine features and response to pulsatile gonadotrophin releasing hormone. Lancet ii: 1375, 1985.

    Article  Google Scholar 

  27. Hughesdon P.E. Morphology and morphogenesis of the Stein-Leventhal ovary and of so-called “hyperthecosis”. Obstet. Gynecol. Survey 37: 59, 1982.

    Article  CAS  Google Scholar 

  28. Van der Meer M., Hompes P.G.A., De Boer J. et al. Cohort size rather than follicle-stimulating hormone threshold level determines ovarian sensitivity in polycystic ovary syndrome. Clin. Endocrinol. Metab. 83: 423, 1998.

    Google Scholar 

  29. Mason H.D., Willis D.S., Beard R.W. et al. Estradiol production by granulosa cells of normal and polycystic ovaries: relationship to menstrual cycle history and concentrations of gonadotrophins and sex steroids in follicular fluids. J. Clin. Endocrinol. Metab. 79: 1355, 1994.

    PubMed  CAS  Google Scholar 

  30. Dong J., Albertini D.F., Nishimori K. et al. Growth differentiation factor-9 is required during early ovarian folliculogenesis. Nature 383: 531, 1996.

    Article  PubMed  CAS  Google Scholar 

  31. Willis D., Mason H.D., Watson H. et al. Premature response to LH of granulosa cells to women with polycystic ovary syndrome. Endocrinology Suppl. 152: 241, 1997.

    Google Scholar 

  32. Almahbobi G., Nagodavithane A., Trounson A.O. Effects of epidermal growth factor, transforming growth factor alpha and androstendione on follicular growth and aromatization in culture. Hum. Reprod. 10: 2767, 1995.

    PubMed  CAS  Google Scholar 

  33. Mason H.D., Margara R., Winston R.M.L. et al. Inhibition of estradiol production by epidermal growth factor in human granulosa cells of normal and polycystic ovaries. Clin. Endocrinol. 33: 511, 1990.

    Article  CAS  Google Scholar 

  34. Bendell J.J., Dorrington J.H. Epidermal growth factor influences growth and differentiation of rat granulosa cells. Endocrinology 127: 533, 1990.

    Article  PubMed  CAS  Google Scholar 

  35. Maruo T., Ladnes-Lave C.A., Samoto T. et al. Expression of epidermal growth factor and its receptor in the human ovary during follicular growth and regression. Endocrinology 132: 924, 1993.

    PubMed  CAS  Google Scholar 

  36. Mason H.D., Carr L., Leake R., Franks S. Production of transforming growth factor alpha by normal and polycystic ovaries. Clin. Endocrinol. Metab. 80: 2053, 1995.

    CAS  Google Scholar 

  37. Volpe A., Coukos G., D’Ambrogio G. et al. Follicular fluid steroid and epidermal growth factor content, and in vitro estrogen release by granulosa luteal cells from patients with polycystic ovaries in an IVF/ET program. Eur. J. Obstet. Gynacol. Reprod. Biol. 42: 195, 1991.

    Article  CAS  Google Scholar 

  38. Cataldo N.A. Insulin-like growth factor binding proteins: do they play a part in polycystic ovary syndrome? Sem. Reprod. Endocrinol. 15: 123, 1997.

    Article  CAS  Google Scholar 

  39. Hsu S.Y., Lai R.J., Finegold M., Hsueh A.J. Targeted overexpression of Bcl-2 in ovaries of transgenic mice leads to decreased follicle apoptosis, enhanced folliculogenesis and increased germ cell tumorigenesis. Endocrinology 137: 4837, 1996.

    PubMed  CAS  Google Scholar 

  40. Ma Y.J., Dissen G.A., Merlino G. et al. Overexpression of a human transforming growth factor alpha (TGF-alpha) transgene reveals a dual antagonistic role of TGF-alpha in female sexual development. Endocrinology 135: 1392, 1994.

    PubMed  CAS  Google Scholar 

  41. Tilly J.L., Billig H., Kowalski K.I., Hsueh A.J. Epidermal growth factor and basic fibroblast growth factor suppress the spontaneous onset of apoptosis in cultured rat ovarian granulosa cells and follicles by a tyrosine kinase dependent mechanism. Mol. Endocrinol. 6: 1942, 1992.

    PubMed  CAS  Google Scholar 

  42. Almahbobi G., Misajon A., Hutchinson P. et al. Hyperexpression of epidermal growth factor receptors in granulosa cells from women with polycystic ovaries. Fertil. Steril. In press.

  43. Aharoni D., Meiri I., Atzmon R. et al. Differential effect of components of the extracellular matrix on differentiation and apoptosis. Curr. Biol. 7: 43, 1997.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Fertility Unit, Department of Ob/Gyn, Rabin Medical Center, Hasharon Hospital, Petah Tikva, 49372, Petah Tikva, Israel

    Roy Homburg

  2. Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, 76100, Israel

    A. Amsterdam

  3. Sackler Medical School, Tel Aviv University, Tel Aviv, Israel

    Roy Homburg

Authors
  1. Roy Homburg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Amsterdam
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Homburg, R., Amsterdam, A. Polycystic ovary syndrome — loss of the apoptotic mechanism in the ovarian follicles?. J Endocrinol Invest 21, 552–557 (1998). https://doi.org/10.1007/BF03350780

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03350780

Key-words

Search

Navigation