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Effect of Progestin on the Ovarian Epithelium of Macaques: Cancer Prevention Through Apoptosis?

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham; Division of Reproductive Endocrinology. Department of Obstetrics and Gynecology, Duke University Medical Center, Durham and Laboratory of Reproductive and Development Toxicology. National Institute for Environmental Health Science, National Institutes of Health, Research Triangle Park: Department of Comparative Medicine, Bowman Gray School of Medicine, Winston-Salem: Department of Pathology, Duke University Medical Center, Durham: Division of Reproductive Endocrinology, University of North Carolina Medical Center, Chapel Hill; Department of Bistatistics, Duke Comprehensive Cancer Center. Duke University Medical Center, Durham; Division of Reproductive Biology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Caroliona; DUMC 3079, Division of Gynecologic Oncology, Department of OB/GYN, Duke University Medical Center, Durham, NC 27710

David K. Walmer, MD, PhD

Mark Cline, DVM, PhD

Hannah Krigman, MD

Bruce A. Lessey, MD, PhD

Regina S. Whitaker, BS

Richard Dodge, MS

Claude L. Hughes, MD, PhD

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham; Division of Reproductive Endocrinology. Department of Obstetrics and Gynecology, Duke University Medical Center, Durham and Laboratory of Reproductive and Development Toxicology. National Institute for Environmental Health Science, National Institutes of Health, Research Triangle Park: Department of Comparative Medicine, Bowman Gray School of Medicine, Winston-Salem: Department of Pathology, Duke University Medical Center, Durham: Division of Reproductive Endocrinology, University of North Carolina Medical Center, Chapel Hill; Department of Bistatistics, Duke Comprehensive Cancer Center. Duke University Medical Center, Durham; Division of Reproductive Biology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Caroliona

Objective: The apoptosis pathway is a vital mechanism in vivo that functions to eradicate genetically damaged cells prone to malignancy. The purpose of this study was to determine whether oral contraceptives, which confer significant protection against subsequent epithelial ovarian cancer, induce apoptosis in the ovarian epithelium.

Methods: Female cynomologus macaques (N = 75) were randomized to receive a diet for 35 months containing either no hormones, the oral contraceptive Triphasil (Wyeth-Ayerst Laboratories, Philadelphia, PA), the estrogenic component of Triphasil (ethinyl estradiol) alone, or the progestin component of Triphasil (levonorgestrel) alone, each administered in a cyclic fashion. At study termination, the animals underwent ovariectomy and the ovarian epithelium was examined morphologically and immunihistochemically for apoptosis. The percentage of ovarian epithelial cells undergoing apoptosis was measured in each animal and compared between the treatment groups.

Results: The median percentage of ovarian epithelial cells undergoing apoptosis by treatment was control (3.8%), ethinyl estradiol (1.8%), Triphasil (14.5%), and levonorgesrel (24.9%). Compared with control and ethinyl estradiol-treated monkeys, a statistically significant increase in the proportion of apoptotic cells was noted in the ovarian epithelium of monkeys treated with the oral contraceptive Triphasil (P .01) or levonorgestrel (P < .001), with a maximal effect (six-fold) seen in the group treated with levonorgestrel alone.

Conclusion: Oral contraceptive progestin induces apoptosis in the ovarian epithelium. Given the importance of the apoptosis pathway for cancer prevention, an effective chemopreventive strategy may be possible using progestins or other agents that selectively induced apoptosis in the ovarian epithelium to prevent the development of ovarian cancer.

Key Words: Progetins • apoptosis • ovarian cancer • oral contraceptives

Journal of the Society for Gynecologic Investigation, Vol. 5, No. 5, 271-276 (1998)
DOI: 10.1177/107155769800500508


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