Progestin-induced apoptosis in the Macaque ovarian epithelium: differential regulation of transforming growth factor-beta.
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-beta1 or TGF-beta2 plus TGF-beta3 (TGF-beta2/3) 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-beta1 and a concomitant increase in the expression of the TGF-beta2/3 isoforms in the ovarian epithelium (P<.001), 2) an increase in the expression of TGF-beta2/3 in the hilar vascular endothelium (P<.001), and 3) a marked decrease in TGF-beta2/3 expression in granulosa cells (P<.001). The apoptotic index of the ovarian epithelium was highly associated with the change in expression from TGF-beta1 (P<.001) to TGF-beta2/3 (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.
Rodriguez
Gustavo C
GC
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA. grodriguez@enh.org
Nagarsheth
Nimesh P
NP
Lee
Karen L
KL
Bentley
Rex C
RC
Walmer
David K
DK
Cline
Mark
M
Whitaker
Regina S
RS
Isner
Pam
P
Berchuck
Andrew
A
Dodge
Richard K
RK
Hughes
Claude L
CL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D003278:Contraceptives, Oral, Hormonal / Q000494:pharmacology; D004848:Epithelium / Q000187:drug effects; D005260:Female; D007150:Immunohistochemistry; D008252:Macaca fascicularis; D010053:Ovary / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011372:Progestins / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D003278:Contraceptives, Oral, Hormonal; D011372:Progestins; D016212:Transforming Growth Factor beta