Effect of progestin on the ovarian epithelium of macaques: cancer prevention through apoptosis?
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 cynomolgus 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 immunohistochemically 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 levonorgestrel (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 < or = .01) or levonorgestrel (P < .001), with a maximal effect (six-fold) seen in the group treated with levonorgestrel alone.


CONCLUSIONS
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 induce apoptosis in the ovarian epithelium to prevent the development of ovarian cancer.
Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC 27710, USA.
G C
GC
Rodriguez
D K
DK
Walmer
M
M
Cline
H
H
Krigman
B A
BA
Lessey
R S
RS
Whitaker
R
R
Dodge
C L
CL
Hughes
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects; D004997:Ethinyl Estradiol / Q000008:administration & dosage / Q000494:pharmacology; D019304:Ethinyl Estradiol-Norgestrel Combination / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D016912:Levonorgestrel / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D008252:Macaca fascicularis; D010051:Ovarian Neoplasms / Q000517:prevention & control*; D010053:Ovary / Q000166:cytology* / Q000187:drug effects*
D004997:Ethinyl Estradiol; D016912:Levonorgestrel; D019304:Ethinyl Estradiol-Norgestrel Combination