Why do Oral Contraceptives Prevent Ovarian Cancer?
Condition: Ovarian Cancer Risk; Risk-reducing Surgery; Fallopian Tube Fimbriae; Ovarian Cortical Inclusion Cysts
MeSH terms: Ovarian Neoplasms; Carcinoma, Ovarian Epithelial
Study type: Interventional
Phase: Early Phase 1

Summary: 
      Use of oral contraceptives (OCs) reduces a woman's risk of ovarian cancer very significantly
      and the protective effect continues for at least 25 years after use of OCs is stopped; the
      mechanisms of how this occurs are not understood. We are proposing here to directly study the
      effect of OCs on the fallopian tube and inclusion cysts within the ovary - sites from which
      most ovarian cancers are thought to arise - in order to better understand the mechanistic
      basis for OC protection against ovarian cancer. We think the protection results from reduced
      cell proliferation. It will lay the foundation for further studies to ensure that the
      protection against ovarian cancer afforded by 'traditional' OCs is not lost with alterations
      in OC formulation, and, if possible, to guide development of OC formations to improve further
      on the protection afforded by OCs.
    

Detailed description: 
      Five-year survival for invasive epithelial ovarian cancer (ovarian cancer) is less than 50%
      because most women are diagnosed at an advanced stage. However, there is an effective
      chemoprevention strategy. Meta-analysis of epidemiological studies shows an approximately 40%
      reduction in risk of ovarian cancer with 5 years of oral contraceptive (OC) use. The
      protective effect increases significantly with duration of OC use and continues for at least
      25 years after use of OCs is stopped. The mechanism(s) underlying this protective effect are
      not understood. One hypothesis is that protection is achieved by blocking ovulation, but
      growing evidence suggests that it may be related to promoting a favorable progestagenic
      environment. OC use would protect if the hormonal exposure while on OCs was less stimulatory
      to the possibly different types of cells of origin of ovarian cancer than the hormonal
      exposure in normal ovulatory cycles. Exposure to progestins is higher while on OCs than in
      normal cycling and this could explain the protective effect. We propose that a major source
      of the protection from OC use is due to their significantly reducing cell proliferation in
      the fallopian tube fimbriae (FTF) and in ovarian cortical inclusion cysts (CICs), two likely
      cells of origin for ovarian cancer. Proliferating cell populations are more susceptible to
      carcinogenic effects with the rise in cancer risk with cell proliferation being secondary to
      increased chances of mutation and progression. FTF proliferation has been reported to be
      almost confined to the follicular phase of the menstrual cycle with virtually no
      proliferation within a few days after ovulation and our preliminary data show the same
      pattern - OCs could thus protect against ovarian cancers arising in the FTF by mimicking the
      luteal phase of the cycle when progesterone exposure is high. Whether such changes occur in
      CICs is not known. Cell proliferation within different types of CICs during the menstrual
      cycle has not been studied. The effect of OCs on proliferation within the FTF and CICs has
      also not been studied. We are proposing to determine the effect of a 'traditional' high
      progestin dose OC on cell proliferation in the FTF and CICs in women undergoing a
      risk-reducing bilateral salpingo-oophorectomy (RR-BSO), and to compare these proliferation
      rates to the rates during the normal menstrual cycle of women also undergoing an RR-BSO. The
      results of this study will provide crucial information regarding the relationship between OC
      use and protection against ovarian cancer. It will lay the foundation for further studies
      examining the effects of lower progestin dose OCs and OCs with newer progestin formulations.
      Our long-term goal in studying the mechanism of OC protection is to determine whether it is
      likely that the protection against ovarian cancer afforded by OCs will be lost with
      alterations in OC formulation in terms of dose or type of progestin used, and, if possible,
      to guide development of OC formations to improve further on the protection afforded by OCs.
    

Intervention name(s): OrthoNovum 1/35
Intervention type(s): Drug
Intervention MeSH terms: Norinyl
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: BRCA1; BRCA2; Risk-reducing surgery; Oral Contraceptives