Progestin treatment induces apoptosis and modulates transforming growth factor-beta in the uterine endometrium.
BACKGROUND
Epidemiologic, animal, and human data suggest that progestins are potent endometrial cancer preventive agents. In the ovarian surface epithelium, progestins have been hypothesized to confer a cancer preventive effect via apoptosis and modulation of transforming growth factor-beta (TGF-beta). Given that the ovarian epithelium and endometrium share a common embryologic origin and similar reproductive and hormonal risk factors for malignancy, we tested the hypothesis that progestins confer biological effects in the endometrium similar to those in the ovary.


METHODS
Postmenopausal female macaques (n = 78) were randomized into four groups to receive a diet for 36 months containing no hormone versus conjugated equine estrogen (CEE), medroxyprogesterone acetate (MPA), or CEE + MPA. The endometrium was then examined immunohistochemically for treatment-specific changes using antibodies to activated caspase-3 (for apoptosis), Ki-67 (proliferation), and the TGF-beta1, TGF-beta2, and TGF-beta3 isoforms.


RESULTS
Percentages of caspase-positive endometrial glandular cells were 3- to 5-fold higher in CEE + MPA-treated animals compared with all others (P < 0.05). Caspase-expressing cells were six times more numerous in the endometrial stroma of animals treated with MPA alone relative to other groups (P < 0.0001). Induction of endometrial glandular cell apoptosis in the CEE + MPA-treated group was associated with a dramatic increase in expression of TGF-beta2 and TGF-beta3 in the stromal compartment of the endometrium (P < 0.0001).


CONCLUSIONS
Progestin treatment activates chemopreventive biological effects in the endometrium that are similar to those in the ovarian surface epithelium. These data may facilitate identification of a chemopreventive approach that dramatically lessens the risk of both uterine and ovarian cancer.
Rodriguez
Gustavo C
GC
Division of Gynecologic Oncology, Evanston Northwestern Healthcare, Feinberg School of Medicine, Northwestern University, Suite 1507, Walgreen Building, 2650 Ridge Avenue, Evanston, IL 60201, USA. grodriguez@enh.org
Rimel
B J
BJ
Watkin
William
W
Turbov
Jane M
JM
Barry
Cathy
C
Du
Hongyan
H
Maxwell
George L
GL
Cline
J M
JM
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D005260:Female; D019394:Ki-67 Antigen / Q000378:metabolism; D016015:Logistic Models; D008252:Macaca fascicularis; D017698:Postmenopause; D011372:Progestins / Q000494:pharmacology*; D011446:Prospective Studies; D011897:Random Allocation; D016212:Transforming Growth Factor beta / Q000187:drug effects*
D019394:Ki-67 Antigen; D011372:Progestins; D016212:Transforming Growth Factor beta; D053148:Caspase 3