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

Authors' Affiliations: ¹ Department of Obstetrics and Gynecology-Center for Integrative Science and ² Department of Pathology, University of Chicago, Chicago, Illinois and ³ Brigham Women's Hospital, Harvard Medical School, Boston, Massachusetts

Requests for reprints: Ernst Lengyel, Section of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Chicago, MC 2050, 5841 South Maryland Avenue, Chicago, IL 60637. Phone: 773-702-6722; Fax: 773-702-5411; E-mail: elengyel{at}uchicago.edu.

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.

Key Words: ovarian cancer • prevention • norethindrone • ethinyl estradiol • GnRH agonist • genetic mouse model • combined oral contraception

Commentary

The Monkey, the Hen, and the Mouse: Models to Advance Ovarian Cancer Chemoprevention

Karen H. Lu, Melinda S. Yates, and Samuel C. Mok
Cancer Prevention Research 2009 2: 773-775. [Abstract] [Full Text] [PDF]

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				The Monkey, the Hen, and the Mouse: Models to Advance Ovarian Cancer Chemoprevention Cancer Prevention Research, September 1, 2009; 2(9): 773 - 775.