In the developed world, epithelial ovarian carcinomas represent 85-90% of all ovarian cancers, rank as the fourth or fifth most common cause of cancer-related deaths in women, and are the primary cause of death from gynecological malignancies. Much effort has been made over the years to understand the biology of the surface epithelium in ovaries, in the hope that such information might explain the tendency for these relatively rare ovarian cells to undergo malignant transformation. Histological studies have revealed the growth and function of ovarian epithelial cells to be regulated by paracrine or endocrine pathways. Furthermore, many investigations have begun clarifying which hormones and growth factors may be involved.
The factors that promote the greatest overall risk reduction for ovarian cancer are the following: 1) parity, meaning the number of live births (Risch et al. 1994; Booth et al. 1989), 2) oral contraceptive use (Risch et al. 1983), and 3) breast feeding (Rosenblatt and Thomas 1993). It was indicated that the combination of oral contraceptive formulations with high progestin potency is associated with a greater reduction in ovarian cancer risk than those with low progestin potency (Schildkraut et al. 2002).
It is well known that during pregnancy, progesterone levels are very high, thus suggesting that they serve as a form of protection (Risch 1998). Therefore, conditions associated with high levels of progesterone, such as a multiple pregnancy, have been reported to reduce a woman’s risk of ovarian cancer (Thomas et al. 1998). However, women with progesterone deficiency were found to have a higher risk of ovarian cancer (Modan et al. 1998). Furthermore, progesterone has been shown to inhibit cell growth by inducing apoptosis in normal and malignant human ovarian surface epithelial (HOSE) cells in vitro and in vivo (Bu et al. 1997; Hu and Deng 2000). It has also been shown to reduce the risk of developing ovarian carcinoma in postmenopausal women who have undergone estrogen and progesterone replacement therapy (Schneider and Birkhauser 1995), and it has been clinically used to treat some types of ovarian tumors (Key 1995).
One aspect that is not clear is whether or not the anti-tumor activity of progesterone is due to its ability to induce apoptosis in ovarian cells. Therefore, a study was designed to test the hypothesis that pregnancy might induce apoptosis of HOSE and inclusion cysts by 1) measuring apoptotic cell in inclusion cysts and HOSE, and 2) determining whether progesterone and estradiol affected cell death. Apoptosis or programmed cell death selectively allows certain cell death following many biological signals. It also plays an important role in development and homeostasis. In malignant cells, these physiological apoptotic pathways are often disrobed, and as a result, they acquire uncontrolled cellular survival (Thompson 1995). Thus, apoptosis is one of the most important mechanisms for eliminating genetically damaged cells that have the potential to become malignant.
The HOSE is separated from the hormone and growth factors that are produced by stroma via the collagenous tunica albuginia and a basement membrane. Ovulation and aging-related trapping of HOSE fragments result in surface invaginations and inclusion cysts in the ovarian cortex (Murdoch 1994). Following each ovulation, the HOSE cells proliferate to heal the wound, and this process results in the formation of the crypt in the ovarian surface. These crypts can then penetrate the ovarian stroma and form inclusion cysts that are lined with HOSE cells (Fathalla 1971; Godwin et al. 1993). However, it was indicated that the first step in tumorigenesis of the surface epithelium is the formation of epithelial inclusion cysts derived from crypts or invaginations of the ovarian surface epithelium (Cramer and Welch 1983). Several investigations have indicated that HOSE cells and cells covering inclusion cysts are thought to be a source of epithelial ovarian cancers (Scully 1977). However, the role of inclusion cysts in malignancy is not yet fully understood.
Studies involving HOSE have been limited by the lack of efficient experimental models. However, HOSE cultures of rat, rabbit, and human have been done (Siemens and Auersperg 1988); Adams and Auersperg 1985), but the use of these animals for culture studies is limited due to their small size and low availability of tissue. However, cultures taken from cows have proven more useful.
The cow is a mono-ovular animal that ovulates in a regular pattern in a cycle similar to that of human females. Bovine ovaries present a useful model for studying biology of HOSE and inclusion cysts and their interaction. Normal gestation for cows average approximately 278-284 days. During pregnancy, gonadotropin levels in the cow are extremely low (Morrow et al. 1969). Estrogen levels are low in the first month, gradually rising to a transient peak in the sixth week. After the first trimester, the estrogen levels increase again, consistently rising until the eighth month, when they level off for about two weeks and then rapidly increase until parturition (Randel and Erb 1971; Randel et al. 1971; Erb et al. 1970).