TY - JOUR
T1 - Progestin-induced apoptosis in the Macaque ovarian epithelium
T2 - Differential regulation of transforming growth factor-β
AU - Rodriguez, Gustavo C.
AU - Nagarsheth, Nimesh P.
AU - Lee, Karen L.
AU - Bentley, Rex C.
AU - Walmer, David K.
AU - Cline, Mark
AU - Whitaker, Regina S.
AU - Isner, Pam
AU - Berchuck, Andrew
AU - Dodge, Richard K.
AU - Hughes, Claude L.
PY - 2002/1/2
Y1 - 2002/1/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0037005938&partnerID=8YFLogxK
M3 - Article
C2 - 11773282
AN - SCOPUS:0037005938
SN - 0027-8874
VL - 94
SP - 50
EP - 60
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 1
ER -