Why do Oral Contraceptives Prevent Ovarian Cancer?

June 24, 2020 updated by: Celeste Pearce, University of Michigan

Mechanisms of Prevention of Ovarian Cancer by Oral Contraceptives

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

52

Phase

  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • British Columbia
      • Vancouver, British Columbia, Canada, V6T 1Z3
        • UBC BC Cancer Agency
  • United States
    • California
      • Los Angeles, California, United States, 90089
        • USC Keck School of Medicine
    • Michigan
      • Ann Arbor, Michigan, United States, 48109
        • University of Michigan

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

30 years to 45 years (ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  • Premenopausal
  • 30 and 45 years of age
  • Scheduled to undergo a laproscopically conducted RR-BSO, risk reducing salpingectomy, salpingectomy for sterilization, or salpingectomy with hysterectomy for non-cancer related conditions
  • Have at least one ovary

Exclusion Criteria:

  • Past hysterectomy
  • Past diagnosis of ovarian cancer
  • Use of Tamoxifen, Raloxifene or hormone replacement therapy in the past 3 months
  • Use of Chemotherapy in the last 6 months

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: BASIC_SCIENCE
  • Allocation: NON_RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
No Intervention: No intervention
No intervention.
Active Comparator: OrthoNovum 1/35
Drug: OrthoNovum 1/35

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Differences in cell proliferation as measured by Ki67 immunohistochemical analysis in the fallopian tube fimbriae of women on the OC arm compared to women on the no treatment arm.
Time Frame: Cell proliferation (Ki67) will be measured in the specimen that is removed as part of the patients surgery (the surgery is not a study procedure).
Cell proliferation (Ki67) will be measured in the specimen that is removed as part of the patients surgery (the surgery is not a study procedure).

Secondary Outcome Measures

Outcome Measure
Time Frame
Cell proliferation as measured by Ki67 immunohistochemical analysis in ovarian cortical inclusion cysts of women on the OC arm compared to women on the no treatment arm.
Time Frame: Cell proliferation (Ki67) will be measured in the tissue removed as part of the surgery (the surgery is not a study procedure)
Cell proliferation (Ki67) will be measured in the tissue removed as part of the surgery (the surgery is not a study procedure)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Michigan

Collaborators

National Cancer Institute (NCI)

Investigators

  • Principal Investigator: Celeste L Pearce, PhD, University of Michigan

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 1, 2014

Primary Completion (Actual)

June 1, 2018

Study Completion (Actual)

June 1, 2018

Study Registration Dates

First Submitted

May 15, 2014

First Submitted That Met QC Criteria

June 2, 2014

First Posted (Estimate)

June 4, 2014

Study Record Updates

Last Update Posted (Actual)

June 25, 2020

Last Update Submitted That Met QC Criteria

June 24, 2020

Last Verified

June 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • OC Prevention
  • 1R21CA178571-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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