Epithelial ovarian cancer in women originates from the ovarian surface epithelium in 85% of cases. During mammalian reproductive phases – estrous (cycling), anoestrous, and pregnancy – drastic tissue modulation and reorganization of ovarian epithelium take place under tight regulation of gonadotropins, localized growth factors, and steroidal hormones. The main aim of the investigation was to elucidate a suppressive role of progesterone during pregnancy on directly surface epithelial cells proliferation that may otherwise become neoplastic, or by initiating apoptosis during an estrous cycle or pregnancy to enable phagocytosis of mutagenized/inflamed cells.
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In the first experiment, oestrous (cycling), anoestrous and pregnant ewes were selected to evaluate whether OSE and follicular granulosa cells proliferation is affected by the reproductive stages of the animal. For this purpose, the level of proliferation was tested immunohistochemically using two nuclear protein markers, PCNA and Ki-67. Further, based on the morphological appearance of granulosa cells, the frequency of primordial, transitory, primary, preantral, and antral follicles was determined in the three groups of animals.
We discussed the role of progesterone produced in the corpus luteum in suppressing follicular development during pregnancy. Pregnancy retarded late follicle growth to atresia and suppressed epithelial and granulosal proliferation, while the opposite happened in the cycling animals. Epithelial cell rupture and re-generation enhanced the hormonal mitogenic action on epithelial cells, which exhibited the highest proliferation over the corpus luteum.
In each ovulatory cycle, the OSE cells are exposed to the follicular fluid which contains a mixture of high levels of steroids, growth factors, and proteins. Cells of OSE express multiple hormone receptor genes, including those encoding for receptors of steroidal and peptidal hormones and localized growth factors. To ascertain the direct effect of the hormones, especially estradiol, progesterone, and insulin-like growth factor (IGF), we have chosen ovine cultured OSE cells grown in a serum-free medium. OSE cells proliferation was measured under the response of fetal calf serum (FCS), fluids from bovine middle and large follicles, and an extract of bovine corpora lutea. To understand whether steroidal hormones in tissue samples were responsible, the fluids were cleaned of steroids by passing through charcoal and yet the proliferative influence prevailed.
Also, to confirm that factors other than steroids may be responsible for in vitro proliferative activity, cultured OSE cells were treated with recombinant human IGF-1, estradiol, and progesterone at different concentrations. Only the gonadotropin stimulated IGF and none of the steroidal hormones were found to accelerate epithelial proliferation. The surface concentration of gondotropin receptors, which up-regulate growth factors, increased before and after ovulation, at which time the in vivo epithelial proliferation also peaked.
Elevated progesterone concentration during pregnancy and the use of progesterone-like contraceptives are known to reduce ovarian cancers. The third experiment was undertaken to decipher whether or not there is any relationship between progesterone (also estrogen)-mediated OSE apoptosis and expression of P53, a cell-cycle arresting protein, and potential tumor suppressor. For this, bovine model was chosen due to similarities with the human reproductive cycle (low ovulation rate).
The in situ apoptosis index was determined during oestrous, and at mid and late-pregnancy stages. Pregnancy-caused inhibition of epithelial proliferation in the bovine model was attributed to higher apoptotic destruction of mitogenic and inflamed cells, thereby evading neoplasia. Cultured epithelial cells also exhibited profound apoptosis with added progesterone. Because P53/p53 gene expression over the corpus luteum producing progesterone also increased, progesterone-mediated apoptosis is mediated through an up-shift of P53 synthesis.
GnRH substituents have wide-scale applications in treating diverse categories of reproduction-related cancers that are associated with the release of gonadotropin from the pituitary. In the final experiment, ovaries from marmoset monkeys collected at specific stages of the ovulatory cycle, during pregnancy, and after treatment with a gonadotropin-releasing hormone, antagonist was studied to investigate further the regulation of OSE proliferation in a non-human primate model. Epithelial proliferation was low in ovaries with low levels of follicular growth and in areas of active ovaries adjacent to immature follicles.
However, there was a marked increase in OSE proliferation in the area of the pre-ovulatory follicle and early corpus lteum. Proliferation was suppressed in ovaries from pregnant marmosets. Cuboidal shape of the epithelium was attained in the invaginating inclusion cysts and post-ovulatory ruptured and over corpus luteum where cells undergo rapid division, whereas squamous type cells were normally seen in the resting epithelium during pregnancy or at the beginning of the oestrous phase. Inhibition of gonadotropin secretion by treatment with a gonadotropin-releasing hormone antagonist also markedly inhibited the epithelial proliferation.
Based on these investigations in model animals we propose that in women pregnancy and progesterone-based contraceptives alleviate epithelial proliferation and reduce the chance of epithelial ovarian cancers, either by suppressing the production of gonadotropins and concomitant localized growth factors – IGF, HGF, etc. and/or by enhancing the P53-mediated apoptosis of damaged and mitogenic cells arising from repeated ovulations.