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

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Abstract

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.

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Authors and Affiliations

  1. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, 27710, USA

    Gustavo C. Rodriguez MD, 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

  2. Division of Reproductive Endocrinology. Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, USA

    Gustavo C. Rodriguez MD, 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

  3. Laboratory of Reproductive and Development Toxicology, National Institute for Environmental Health Science, National Institutes of Health, Research Triangle Park, USA

    Gustavo C. Rodriguez MD, 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

  4. Department of Comparative Medicine, Bowman Gray School of Medicine, Winston-Salem, USA

    Gustavo C. Rodriguez MD, 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

  5. Department of Pathology, Duke University Medical Center, Durham, USA

    Gustavo C. Rodriguez MD, 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

  6. Division of Reproductive Endocrinology, University of North Carolina Medical Center, Chapel Hill, USA

    Gustavo C. Rodriguez MD, 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

  7. Department of Biostatistics, Duke Comprehensive Cancer Center, Duke University Medical Center, Durham, USA

    Gustavo C. Rodriguez MD, 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

  8. Division of Reproductive Biology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Caroliona, USA

    Gustavo C. Rodriguez MD, 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

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  1. Gustavo C. Rodriguez MD
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  2. David K. Walmer MD, PhD
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Additional information

Supported by grants from The American Cancer Society and The Berlex Foundation.

The authors thank Dr. M. Adams for the generous provision of ovarian tissues from his primate study supported by National Instirutes of Health Grant R01HL46409 from the National Heart, Lung, and Blood Institute.

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Rodriguez, G.C., Walmer, D.K., Cline, M. et al. Effect of Progestin on the Ovarian Epithelium of Macaques: Cancer Prevention Through Apoptosis?. Reprod. Sci. 5, 271–276 (1998). https://doi.org/10.1177/107155769800500508

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