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JNCI Journal of the National Cancer Institute 2002 94(1):50-60; doi:10.1093/jnci/94.1.50
© 2002 by Oxford University Press
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Journal of the National Cancer Institute, Vol. 94, No. 1, 50-60, January 2, 2002
© 2002 Oxford University Press

ARTICLE

Progestin-Induced Apoptosis in the Macaque Ovarian Epithelium: Differential Regulation of Transforming Growth Factor-{beta}

Gustavo C. Rodriguez, Nimesh P. Nagarsheth, Karen L. Lee, Rex C. Bentley, David K. Walmer, Mark Cline, Regina S. Whitaker, Pam Isner, Andrew Berchuck, Richard K. Dodge, Claude L. Hughes

Affiliations of authors: G. C. Rodriguez, R. S. Whitaker, P. Isner, A. Berchuck (Division of Gynecologic Oncology, Department of Obstetrics and Gynecology), N. P. Nagarsheth, K. L. Lee (Department of Obstetrics and Gynecology), R. C. Bentley (Department of Pathology), D. K. Walmer (Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology), R. K. Dodge (Department of Biostatistics, Duke Comprehensive Cancer Center), Duke University Medical Center, Durham, NC; M. Cline, Section of Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC; C. L. Hughes, Department of Obstetrics and Gynecology, Duke University Medical Center and Avalon Medical Group, Chapel Hill, NC.

Correspondence to: Gustavo C. Rodriguez, M.D., Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Rm. 1315, Evanston Northwestern Healthcare, 2650 Ridge Rd., Evanston, IL 60201 (e-mail: grodriguez{at}enh.org).

Background: Oral contraceptive (OC) use is associated with a reduced risk of ovarian cancer. An OC component, progestin, induces apoptosis in the primate ovarian epithelium. One regulator of apoptosis is transforming growth factor-{beta} (TGF-{beta}). We determined the effect of progestin on TGF-{beta} expression in the primate ovarian epithelium and examined the relationship between TGF-{beta} expression and apoptosis. Methods: Female cynomolgus macaques were randomly assigned to receive a diet for 35 months containing no hormones (n = 20); the OC Triphasil (n = 17); or each of its constituents, ethinyl estradiol (estrogen, n = 20) or levonorgestrel (progestin, n = 18 ), alone. Ovarian sections were immunostained with monoclonal antibodies against TGF-{beta}1 or TGF-{beta}2 plus TGF-{beta}3 (TGF-{beta}2/3) isoforms. The expression of TGF-{beta} isoforms in four ovarian compartments (epithelium, oocytes, granulosa cells, and hilar vascular endothelium) was compared among treatment groups. The association between TGF-{beta} expression and apoptosis, as determined by morphology and histochemistry, was examined in ovarian epithelium. All statistical tests were two-sided. Results: Compared with ovaries from the control and estrogen-only-treated monkeys, the ovaries of progestin-treated monkeys showed 1) a marked decrease in the expression of TGF-{beta}1 and a concomitant increase in the expression of the TGF-{beta}2/3 isoforms in the ovarian epithelium (P<.001), 2) an increase in the expression of TGF-{beta}2/3 in the hilar vascular endothelium (P<.001), and 3) a marked decrease in TGF-{beta}2/3 expression in granulosa cells (P<.001). The apoptotic index of the ovarian epithelium was highly associated with the change in expression from TGF-{beta}1 (P<.001) to TGF-{beta}2/3 (P<=.002) induced by progestin treatment. Conclusions: Progestin induces differential regulation in the ovarian epithelium of TGF-{beta}, a change in the expression of which is highly associated with apoptosis. These data suggest a possible biologic mechanism for the protective association between OC use and reduced ovarian cancer risk.


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