Editorial

Gustavo Rodriguez, MD, Associate Professor, Division of Gynecologic Oncology, Duke University Medical Center, Durham, NC

The pathogenesis of epithelial ovarian cancer is not completely understood. However, it is commonly believed that ovulation, with its associated disruption and subsequent repair of the ovarian epithelium can lead to the acquisition of genetic damage in ovarian epithelial cells and that sufficient genetic damage can lead to ovarian cancer in susceptible individuals. Under this model, reproductive and hormonal factors such as oral contraceptive pill use and pregnancy have been presumed to alter ovarian cancer risk mainly via their impact on ovulation. The so called "incessant ovulation" hypothesis for ovarian cancer is supported by a large volume of epidemiologic evidence linking ovulation with ovarian cancer risk, and is further supported by the finding that spontaneous ovarian cancers arise frequently in poultry hens, which ovulate daily. Although this hypothesis is attractive, it fails to completely explain the marked protective effect conferred by pregnancy and oral contraceptives against ovarian cancer risk, a degree of protection that is disproportionately greater than that expected simply on the basis of the number of ovulatory cycles that are inhibited. Hormonal factors must be impacting ovarian cancer risk through additional mechanisms unrelated to ovulation inhibition.

The normal ovarian epithelium expresses receptors for estrogen, progestin and androgen, and there is a growing body of evidence that these reproductive hormones can have potent biologic effects directly on the ovarian epithelium, possibly impacting ovarian cancer risk. Our group has demonstrated that progestins induce apoptosis in the ovarian epithelium. The apoptosis pathway is one of the most important molecular mechanisms in vivo for cancer prevention, and has been shown to mediate the effects of a number of well known cancer preventive agents. The finding that this pathway is activated by progestins makes it possible that apoptotic effects on the ovarian epithelium may be a major mechanism underlying the protective effects of pregnancy and pill use against ovarian cancer. Further research is necessary to further define the biologic effect of progestins in the ovaries of women and to identify the optimal formulations that maximize ovarian cancer prevention.

Ovarian Cancer Protection Through Progestin-Induced Apoptosis

Remarkable progress is being made in the fight against ovarian cancer, as ongoing biologic research and recent data from landmark trials shed new light on treating and preventing the disease. A major public health issue, ovarian cancer strikes one in 55 women in the United States and ranks as the fifth leading cause of cancer-related death among women-more than all other gynecologic malignancies combined. A number of pathogenic hypotheses to explain the disease have been postulated, including incessant ovulation, which holds ovarian cancer to be the end result of DNA damage incurred during the epithelial tearing and regeneration that occurs with each ovulation.

Studies have shown that oral contraceptive pill use lowers ovarian cancer risk, and the underlying mechanism has been presumed to be related to the ability of these agents to inhibit ovulation, thereby decreasing ovarian epithelial damage. New data, however, suggests that oral contraceptive hormones, namely the progestin component, interact with the ovarian epithelium and activate molecular pathways that are cancer preventive. The resulting hypothesis is that progestin mediated biologic effects may be a major component underlying the protective effect of the pill.

Presenting new research, Gustavo Rodriguez, MD, Associate Professor, Division of Gynecologic Oncology, Duke University Medical Center, Durham, NC discussed scientific evidence demonstrating activation of anticancer effects by progestins in ovarian epithelial cells. Expert researchers presented their data during an industry-sponsored symposium, "Clinical Update: Ovarian Cancer Protection Through Progestin-Induced Apoptosis", at the XVI FIGO World Congress of Gynecology and Obstetrics, held in Washington, DC, September 3- 8, 2000.

Countering the incessant ovulation theory, Dr. Rodriguez said, "... new animal research suggests the protective effect of OC's may not accrue solely from the indirect action of stopping ovulation. Rather, it appears that biologic effects related to progestins may be conferring cancer prevention via induction of programmed cell death (apoptosis) in the ovarian epithelium." Further, this effect appears to be highly associated with up-regulation of Transforming Growth Factor Beta (TGF-beta). Both molecular events have been strongly implicated in cancer prevention, and are believed to underlie the protective effects of other known chemopreventive agents such as retinoids and tamoxifen.

Dr. Rodriguez based his comments on results of a three-year study (J Soc Gynecol Investig, 1998, 5(5):271-6) in which he and his colleagues at Bowman Gray Medical School studied the biologic effects of combination levonorgestrel-ethinyl estradiol and each of its components on the ovaries of primates to determine if the OC has a direct effect on inducing the apoptotic pathway in the ovarian epithelium.

In the study, 75 female Cynomolgus macaques were randomized to a diet containing either no hormones, combination levonorgestrel-ethinyl estradiol, ethinyl estradiol alone, or levonorgestrel alone, each administered in a cyclic fashion.

At study termination, the ovarian epithelium of monkeys 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 showed the median percentage of ovarian epithelial cells undergoing apoptosis by treatment was 3.8 percent in controls, 1.5 percent in the ethinyl estradiol group, 14.5 percent in the combination levonorgestrel-ethinyl estradiol group, and 24.9 percent in the levonorgestrel group. 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 combination levonorgestrel-ethinyl estradiol (p = 0.01) or levonorgestrel (p < 0.001), with a maximal effect seen in the group treated with levonorgestrel alone.

With immunohistochemical staining, the researchers noted apoptotic cells were rarely seen in the control and ethinyl estradiol-treated groups, whereas the ovarian epithelium of monkeys who had received either combination levonorgestrel-ethinyl estradiol or levonorgestrel alone, contained numerous apoptotic cells and demonstrated a tendency for patches of the ovarian surface to be either devoid of epithelium or contain epithelial cells with sparse cytoplasm that appeared to be detaching from the ovarian surface?an observation particularly noticeable in the group receiving levonorgestrel alone.

Pointing out that the study is the first to demonstrate induction of apoptosis by synthetic progestin in vivo, Dr. Rodriguez hypothesized that as a result of enhanced apoptosis, genetically damaged ovarian epithelial cells may be more likely to be removed from the ovarian surface, rather than persist and potentially develop into epithelial ovarian carcinoma.

In conjunction with Dr. Rodriguez's presentation on biologic effects of OC's, James Fiorica, MD, Professor of Obstetrics and Gynecology, College of Medicine, University of South Florida, Tampa said the protective benefits of OC's have been long recognized and documented in various clinical trials dating back to the late 1960s. Key among them was the Cancer and Steroid Hormone Study (CASH), a multicenter trial organized by the Centers for Disease Control throughout the US. In all, 546 women ages 20-54 were evaluated to see if OC formulations made a difference in decreasing the incidence of ovarian cancer, and if histology changes were evident between hormone versus non-hormone users. The relative risk of ovarian cancer for OC users was 0.6 compared to nonusers, researchers concluded, with protective effects from ovarian cancer evident up to 15 years after subjects discontinued the pill.

Other supporting studies discussed included the WHO Collaborative Study of Neoplasia and Steroid Contraceptives, the Northern Italy-Milan Study, and a meta-analysis by Hankinson et al. (Obstet Gynecol, 1992, 70:708-14). As well, results of a study by Narod et al. (NEJM, 1998, 339:424-8), showed ovarian cancer risk was reduced by 60 percent in both BRCA1 and BRCA2 patients who had used OC's for = 6 years.

Dr. Fiorica said, "the lower dose OC's are safe and have the same non- contraceptive benefits as high dose formulations, including a decrease in ovarian cancer risk, with a protective effect that continues for up to ten years after use is discontinued. Consequently, we may consider these OC's for primary prevention in high risk individuals such as BRCA1 patients as well as the general population."