Progestin-induced apoptosis in the Macaque ovarian epithelium: Differential regulation of transforming growth factor-β

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

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106 Scopus citations


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-β (TGF-β). We determined the effect of progestin on TGF-β expression in the primate ovarian epithelium and examined the relationship between TGF-β 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-β1 or TGF-β2 plus TGF-β3 (TGF-β2/3) isoforms. The expression of TGF-β isoforms in four ovarian compartments (epithelium, oocytes, granulosa cells, and hilar vascular endothelium) was compared among treatment groups. The association between TGF-β 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-β1 and a concomitant increase in the expression of the TGF-β2/3 isoforms in the ovarian epithelium (P<.001), 2) an increase in the expression of TGF-β2/3 in the hilar vascular endothelium (P<.001), and 3) a marked decrease in TGF-β2/3 expression in granulosa cells (P<.001). The apoptotic index of the ovarian epithelium was highly associated with the change in expression from TGF-β1 (P<.001) to TGF-β2/3 (P≤.002) induced by progestin treatment. Conclusions: Progestin induces differential regulation in the ovarian epithelium of TGF-β, 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.

Original languageEnglish
Pages (from-to)50-60
Number of pages11
JournalJournal of the National Cancer Institute
Issue number1
StatePublished - 2 Jan 2002
Externally publishedYes


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