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Why do Oral Contraceptives Prevent Ovarian Cancer?

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ClinicalTrials.gov Identifier: NCT02155777
Recruitment Status : Active, not recruiting
First Posted : June 4, 2014
Last Update Posted : July 9, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Celeste Pearce, University of Michigan

Brief 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.

Condition or disease Intervention/treatment Phase
Ovarian Cancer Risk Risk-reducing Surgery Fallopian Tube Fimbriae Ovarian Cortical Inclusion Cysts Drug: OrthoNovum 1/35 Early Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 52 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Mechanisms of Prevention of Ovarian Cancer by Oral Contraceptives
Actual Study Start Date : June 2014
Actual Primary Completion Date : June 2018
Estimated Study Completion Date : January 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Ovarian Cancer
Drug Information available for: Binovum

Arm Intervention/treatment
No Intervention: No intervention
No intervention.
Active Comparator: OrthoNovum 1/35
OrthoNovum 1/35
Drug: OrthoNovum 1/35



Primary Outcome Measures :
  1. 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). ]

Secondary Outcome Measures :
  1. 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) ]


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Ages Eligible for Study:   30 Years to 45 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02155777


Locations
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United States, California
USC Keck School of Medicine
Los Angeles, California, United States, 90089
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
Canada, British Columbia
UBC BC Cancer Agency
Vancouver, British Columbia, Canada, V6T 1Z3
Sponsors and Collaborators
University of Michigan
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Celeste L Pearce, PhD University of Michigan

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Responsible Party: Celeste Pearce, Associate Professor, University of Michigan
ClinicalTrials.gov Identifier: NCT02155777     History of Changes
Other Study ID Numbers: OC Prevention
1R21CA178571-01 ( U.S. NIH Grant/Contract )
First Posted: June 4, 2014    Key Record Dates
Last Update Posted: July 9, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Celeste Pearce, University of Michigan:
BRCA1
BRCA2
Risk-reducing surgery
Oral Contraceptives
Additional relevant MeSH terms:
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Ovarian Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site
Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Contraceptives, Oral
Contraceptives, Oral, Combined
Contraceptives, Oral, Hormonal
Contraceptives, Oral, Sequential
Contraceptives, Oral, Synthetic
Carcinoma, Ovarian Epithelial
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Endocrine System Diseases
Gonadal Disorders
Carcinoma
Contraceptive Agents
Norinyl
Norethindrone acetate, ethinyl estradiol, ferrous fumarate drug combination
Norethindrone
Mestranol
Reproductive Control Agents
Physiological Effects of Drugs
Contraceptive Agents, Female
Estrogens
Hormones