Ovulation and Ovarian Cancer

  • Stephen G. Hillier
  • Michael T. Rae
  • Oliver Gubbay
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 617)

Ovarian cancer (OC) most frequently arises from the ovarian surface epithelium (OSE), which comprises a single layer of mesothelial, squamous-to-cuboidal cells covering the entire surface of the ovary (1). This dynamic cellular layer and underlying basement membrane is breached and repaired each time a follicle ovulates, which can happen up to around 400 times in an average woman’s lifetime. It is, therefore, perhaps not surprising that there is a positive association between ovulation and OC and that a majority of OCs arise from the OSE. OC has genetic and environmental aetiologies, and there is growing evidence for inflammatory involvement as well. Ovulation is a natural inflammatory process, the suppression of which by pregnancy, breast-feeding, or oral contraception reduces OC risk. On the other hand, environmental factors and medical conditions associated with ovarian inflammation such as use of talc, endometriosis, ovarian cysts, and hyperthyroidism increase OC risk (2). If inflammation promotes cancer (3,4), we argue that antiinflammation is quite likely to be protective. In this chapter, we rehearse evidence that inflammation is integral to ovulation and consider how associated antiinflammatory mechanisms might impact OC initiation and progression.


Ovarian Cancer Glucocorticoid Receptor Granulosa Cell Ovarian Surface Epithelium Ovarian Cancer Risk 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Auersperg N, Wong AS, Choi KC, et al. (2001) Ovarian surface epithelium: biology, endocrinology, and pathology. Endocr Rev 22:255–88.PubMedCrossRefGoogle Scholar
  2. 2.
    Ness RB, Cottreau C (1999) Possible role of ovarian epithelial inflammation in ovarian cancer. J Natl Cancer Inst 91:1459–67.PubMedCrossRefGoogle Scholar
  3. 3.
    Balkwill F, Charles KA, Mantovani A (2005) Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 7:211–17.PubMedCrossRefGoogle Scholar
  4. 4.
    Fleming JS, Beaugie CR, Haviv I, et al. (2006) Incessant ovulation, inflammation and epithelial ovarian carcinogenesis: revisiting old hypotheses. Mol Cell Endocrinol 247:4–21.PubMedCrossRefGoogle Scholar
  5. 5.
    Espey LL (1994) Current status of the hypothesis that mammalian ovulation is comparable to an inflammatory reaction. Biol Reprod 50:233–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Richards JS, Russell DL, Ochsner S, et al. (2002) Ovulation: new dimensions and new regulators of the inflammatory-like response. Annu Rev Physiol 64:69–92.PubMedCrossRefGoogle Scholar
  7. 7.
    Murdoch WJ, Wilken C, Young DA (1999) Sequence of apoptosis and inflammatory necrosis within the formative ovulatory site of sheep follicles. J Reprod Fertil 117:325–9.PubMedGoogle Scholar
  8. 8.
    Rae MT, Hillier SG (2005) Steroid signalling in the ovarian surface epithelium. Trends Endocrinol Metab 16:327–33.PubMedCrossRefGoogle Scholar
  9. 9.
    Murdoch WJ (1995) Programmed cell death in preovulatory ovine follicles. Biol Reprod 53:8–12.PubMedCrossRefGoogle Scholar
  10. 10.
    Ghahremani M, Foghi A, Dorrington JH (1999) Etiology of ovarian cancer: a proposed mechanism. Med Hypotheses 52:23–6.PubMedCrossRefGoogle Scholar
  11. 11.
    Kirsner RS, Eaglstein WH (1993) The wound healing process. Dermatol Clin 11:629–40.PubMedGoogle Scholar
  12. 12.
    Verrecchia F, Mauviel A (2004) TGF-beta and TNF-alpha: antagonistic cytokines controlling type I collagen gene expression. Cell Signal 16:873–80.PubMedCrossRefGoogle Scholar
  13. 13.
    Yang WL, Godwin AK, Xu XX (2004) Tumor necrosis factor-alpha-induced matrix proteolytic enzyme production and basement membrane remodeling by human ovarian surface epithelial cells: molecular basis linking ovulation and cancer risk. Cancer Res 64:1534–40.PubMedCrossRefGoogle Scholar
  14. 14.
    Rae MT, Niven D, Ross A et al. (2004) Steroid signalling in human ovarian surface epithelial cells: the response to interleukin-1alpha determined by microarray analysis. J Endocrinol 183:19–28.PubMedCrossRefGoogle Scholar
  15. 15.
    Kagan HM, Li W (2003) Lysyl oxidase: properties, specificity, and biological roles inside and outside of the cell. J Cell Biochem 88:660–72.PubMedCrossRefGoogle Scholar
  16. 16.
    Erler JT, Bennewith KL, Nicolau M, et al. (2006) Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 440:1222–6.PubMedCrossRefGoogle Scholar
  17. 17.
    Bukulmez O, Arici A (2000) Leukocytes in ovarian function. Hum Reprod Update 6:1–15.PubMedCrossRefGoogle Scholar
  18. 18.
    Ness RB, Cottreau C (1999) Possible role of ovarian epithelial inflammation in ovarian cancer. J Natl Cancer Inst 91:1459–673.PubMedCrossRefGoogle Scholar
  19. 19.
    Karin M (2006) Nuclear factor-kappaB in cancer development and progression. Nature 441:431–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Coussens LM, Tinkle CL, Hanahan D, et al. (2000) MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell 1:481–90.CrossRefGoogle Scholar
  21. 21.
    Tiano HF, Loftin CD, Akunda J, et al. (2002) Deficiency of either cyclooxygenase (COX)-1 or COX-2 alters epidermal differentiation and reduces mouse skin tumorigenesis. Cancer Res 62:3395–401.PubMedGoogle Scholar
  22. 22.
    Aggarwal BB, Shishodia S, Sandur SK, et al. (2006) Inflammation and cancer: How hot is the link? Biochem Pharmacol 72:1605–21.PubMedCrossRefGoogle Scholar
  23. 23.
    Grosch S, Maier TJ, Schiffmann S, Geisslinger G, et al. (2006) Cyclooxygenase-2 (COX-2)-independent anticarcinogenic effects of selective COX-2 inhibitors. J Natl Cancer Inst 98:736–47.PubMedCrossRefGoogle Scholar
  24. 24.
    Tomlinson JW, Walker EA, Bujalska IJ, et al. (2004) 11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocr Rev 25:831–66.PubMedCrossRefGoogle Scholar
  25. 25.
    Tetsuka M, Thomas FJ, Thomas MJ, et al. (1997) Differential expression of messenger ribonucleic acids encoding 11beta-hydroxysteroid dehydrogenase types 1 and 2 in human granulosa cells. J Clin Endocrinol Metab 82:2006–9.PubMedGoogle Scholar
  26. 26.
    Yong PY, Thong KJ, Andrew R, et al. (2000) Development-related increase in cortisol biosynthesis by human granulosa cells. J Clin Endocrinol Metab 85:728–33.CrossRefGoogle Scholar
  27. 27.
    Tetsuka M, Haines LC, Milne M, et al. (1999) Regulation of 11beta-hydroxysteroid dehydrogenase type 1 gene expression by LH and interleukin 1beta in cultured rat granulosa cells. J Endocrinol 163:417–23.PubMedCrossRefGoogle Scholar
  28. 28.
    Yong PY, Harlow C, Thong KJ, et al. (2002) Regulation of 11beta-hydroxysteroid dehydrogenase type 1 gene expression in human ovarian surface epithelial cells by interleukin-1. Hum Reprod 1:2300–6. Erratum in: Hum Reprod 17:3009.CrossRefGoogle Scholar
  29. 29.
    Rae MT, Niven D, Critchley HO, et al. (2004) Antiinflammatory steroid action in human ovarian surface epithelial cells. J Clin Endocrinol Metab 89:4538–44.PubMedCrossRefGoogle Scholar
  30. 30.
    Fleming JS, Beaugie CR, Haviv I, et al. (2006) Incessant ovulation, inflammation and epithelial ovarian carcinogenesis: revisiting old hypotheses. Mol Cell Endocrinol 247:4–21.PubMedCrossRefGoogle Scholar
  31. 31.
    Langdon SP, Lawrie SS, Hay FG, et al. (1988) Characterization and properties of nine human ovarian adenocarcinoma cell lines. Cancer Res 48:6166–72.PubMedGoogle Scholar
  32. 32.
    Rabbitt EH, Gittoes NJ, Stewart PM, et al. (2003) 11beta-hydroxysteroid dehydrogenases, cell proliferation and malignancy. J Steroid Biochem Mol Biol 85:415–21.PubMedCrossRefGoogle Scholar
  33. 33.
    Gubbay O, Guo W, Rae MT, et al. (2005) Inflammation-associated gene expression is altered between normal human ovarian surface epithelial cells and cell lines derived from ovarian adenocarcinomas. Br J Cancer 92:1927–33.PubMedCrossRefGoogle Scholar
  34. 34.
    Altinoz MA, Korkmaz R (2004) NF-kappaB, macrophage migration inhibitory factor and cyclooxygenase-inhibitions as likely mechanisms behind the acetaminophen- and NSAID-prevention of the ovarian cancer. Neoplasma 51:239–47.PubMedGoogle Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  • Stephen G. Hillier
    • 1
  • Michael T. Rae
  • Oliver Gubbay
  1. 1.The Queen’s Medical Research InstituteUniversity of Edinburgh Center for Reproductive BiologyEdinburghScotland

Personalised recommendations