Effects of Oral Contraceptives or a Gonadotropin-Releasing Hormone Agonist on Ovarian Carcinogenesis in Genetically Engineered Mice

Abstract

Although epidemiologic evidence for the ability of combined oral contraception (OC) to reduce the risk of ovarian cancer (OvCa) is convincing, the biological mechanisms underlying this effect are largely unknown. We conducted the present study to determine if OC also influences ovarian carcinogenesis in a genetic mouse model and, if so, to investigate the mechanism underlying the protective effect. LSL-K-ras G12D/+ Pten loxP/loxP mice were treated with ethinyl estradiol plus norethindrone, contraceptive hormones commonly used in combined OC, or norethindrone alone, or a gonadotropin-releasing hormone agonist. The combined OC had a 29% reduction in mean total tumor weight compared with placebo (epithelial tumor weight, −80%). Norethindrone alone reduced mean total tumor weight by 42% (epithelial tumor weight, −46%), and the gonadotropin-releasing hormone agonist increased mean total tumor weight by 71% (epithelial tumor weight, +150%). Large variations in tumor size affected the P values for these changes, which were not statistically significant. Nonetheless, the OC reductions are consistent with the epidemiologic data indicating a protective effect of OC. Matrix metalloproteinase-2 activity was decreased in association with OC, indicating that OC may affect ovarian carcinogenesis by decreasing proteolytic activity, an important early event in the pathogenesis of OvCa. In contrast, OC increased invasion in a K-ras/Pten OvCa cell line established from the mouse tumors, suggesting that OC hormones, particularly estrogen, may have a detrimental effect after the disease process is under way. Our study results support further investigation of OC effects and mechanisms for OvCa prevention.Despite decades of research, ovarian cancer (OvCa) continues to cause more deaths among women in the United States than any other reproductive cancer (1). Using the best screening methods available (pelvic exam, vaginal ultrasound,, the detection of one case of OvCa requires between 11 and 64 unnecessary surgeries (2, 3). It is therefore widely accepted that given the limitations of screening and our current inability to cure OvCa, prevention is key to a reduction in mortality. Until we are able to cure or consistently diagnose early OvCa, strategies for prevention merit at least as much attention as treatment for the disease.Convincing epidemiologic studies have shown that combined oral contraceptive (OC) use decreases the risk of developing epithelial OvCa more than any other agent studied and the protection conferred is long lasting (4-8). However, the mechanism of this effect is largely unknown. One hypothesis is that OC decreases ovulation resulting in less genetic instability in the ovarian surface epithelial cells from imperfect repair at the ovulation site (9). A second hypothesis is that gonadotropins activate cells, thereby inducing malignant transformation, and that OCs protect against OvCa by decreasing gonadotropin levels (10). There have been few laboratory studies, however, that either confirm the protection co...

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“…17 The SKOV3ip1 and HeyA8 cell lines were provided by Dr. Gordon Mills (MD Anderson Cancer Center, Houston, TX). The IOSE 397 cell line was kindly shared by Dr. Nelly Auersperg (University of British Columbia, Canada).…”

“…17 The effect of treatment was calculated as a percentage of control cell growth obtained from vehicle-treated cells grown in the same plate. Each experiment was conducted in triplicate.…”

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“…When the two mutations were combined, the mice developed metastatic ovarian carcinoma, which often appeared endometrioid. 27,28 The sequence of genetic events in high-grade serouspapillary carcinomas is not as well understood. Clinical experience and a recent study 29 suggest that these tumors grow quickly and disseminate widely within the mesothelial cell-covered peritoneal cavity (or as an effusion in the mesothelial cell covered pleural space).…”

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“…GnRH treatment also increases type I matrix metalloproteinase (MT-1MMP) levels, thereby increasing cells' invasiveness and metastatic potential which increases cell migration and invasion during tumor progression through activation of Rho GTPases and accumulation of p120 catenin, with reversible effects upon inhibition of p120 (Cheung et al, 2010). In vivo, mice treated with a GnRH agonist displayed increased tumor weight (Romero et al, 2009). Thus, while GnRH and its agonists work via G i to decrease cellular growth and proliferation, it also enhances other pathways which promote cellular migration and invasion, essentially increasing metastatic potential.…”