Steroid Hormones and Ovarian Cancer

Abstract

Globally, ovarian cancer is the 6th most common malignancy in developed countries, responsible for 100,300 new cases and 64,500 deaths annually (Jemal et al., 2011). Approximately 90% of ovarian cancers arise within the ovarian surface epithelium (OSE) or the fallopian tube surface epithelium; the remainder of ovarian malignancies develops from other ovarian tissues (sex cord-stromal, germ cell, or mixed cell tumors). The overall prognosis for epithelial ovarian carcinoma (EOC) is poor: Diagnosis is typically late-stage due to the lack of effective screening methods and vague presenting symptoms, with 5-year survival at 40% for stage III and 20% for stage IV patients (Heintz et al., 2006). Despite excellent initial activity, the standard treatment consisting of cytoreductive surgery followed by platinumand taxane-based chemotherapy often fails with a recurrence rate of over 80% in stage III and IV disease. Therefore, novel therapeutic approaches are needed to improve the outcomes in this population. Research efforts have yielded insight into the etiology, signaling mechanisms, and progression of ovarian cancer, yet much remains poorly understood. Physiologically, steroid hormones are intimately involved in ovulation, reproduction, and function of normal OSE cells. There is growing evidence that estrogen, progesterone, and other hormones also play a role in the development and progression of ovarian cancer (Leung & Choi, 2007). “Incessant ovulation” with repetitive injury and repair of OSE and subsequent cumulative DNA damage is one of the hypothesized risk factors for ovarian cancer (Fathalla, 1971), yet this does not explain the occurrence of the majority of ovarian carcinomas well after the reproductive years (Berek & Hacker, 2010). Interestingly, although oral contraceptives (OCs), increasing parity, and prolonged breastfeeding all decrease cumulative risk (Gwinn et al., 1990; Risch et al., 1994), progestin-only contraceptives offer just as much protective benefit as estrogen-containing OCs without prohibiting ovulation (Risch, 1998). Another hypothesis for the development of ovarian cancer, the “gonadotropin hypothesis,” stipulates that gonadotropins contribute to ovarian carcinogenesis through follicle stimulating hormone (FSH)and luteinizing hormone (LH)-mediated excess stimulation of ovarian tissue. This hypothesis is consistent with the protective effect of OCs, and the observation that the majority of cases of epithelial ovarian cancer develop postmenopausally after a surge in gonadotropin levels. In vitro, gonadotropins such as FSH activate mitogenic pathways and stimulate ovarian epithelial cell proliferation (Choi et al., 2002). In addition to gonadotropins, excess androgens and estrogen have also been linked to the progression and possibly development of ovarian cancer. In vivo treatment of mice with