I-44: Long-Term Sequelae of Polycystic OvarySyndrome: Gynecological Cancer

Women with polycystic ovary syndrome (PCOS) have been reported to be at increased risk of a number of gynecological neoplasias, including endometrial, breast, and ovarian cancer. The data supporting an increased risk is almost entirely inferential, based primarily on small case series or shared risk factors. One of the difficulties in exploring the association between these cancers and PCOS, is that they remain primarily diseases of postmenopausal women and present long after PCOS has faded. Only a fraction of cancer cases present in pre-menopausal women, where a concurrent diagnosis of PCOS may exist. The basis for the concerns about long-term sequelae is that women with PCOS have a number of reproductive and metabolic abnormalities. The reproductive abnormalities include chronic anovulation, prolonged exposure to estrogen, progesterone deficiency, and androgen excess, which may contribute to an increased risk for gynecological cancers in which the hormonal milieu is an important contributor to etiology and prognosis. Endometrial cancer is currently thought to be perhaps the best example of a hormone-dependent neoplasia. Endometrial cancer is thought to arise from prolonged exposure to estrogen, without the benefits of progesterone,a condition known as unopposed estrogen. Estrogen is a clear mitogen on the endometrium and leads to proliferation of both the glandular and stromal components. More recently, insulin resistance and hyperinsulinemia have been implicated as contributory agents to a variety of neoplasias. Smaller studies of women with endometrial cancer have shown increased fasting and glucosestimulated insulin levels compared with controls. Another study found a similar result among women with endometrial cancers both in relation to controls and women with other hormone-dependent neoplasias such as breast cancer. A variety of mechanisms has been proposed. Insulin is a powerful mitogenic influence on a variety of tissues including endometrium and breast epithelium, and this proliferative effect may contribute to the appearance of oncogenes and transformation of benign tissue. In vitro studies of cancer cell lines have shown that insulin is mitogenic, and most cell cultures of tumor cells require the presence of insulin in order to survive. Insulin may play a role in the development of estrogen receptor negative endometrial cancers- cancers that usually are more aggressive and have a poorer prognosis. A link between PCOS and cancer of the breast appears probable on both theoretical grounds, although the epidemiological evidence is mixed. An association between PCOS and ovarian cancer seems unlikely, leaving aside the putative association with ovulation-inducing drugs, which is an issue that should not apply to the modern approach to unifollicular ovulation induction in patients with PCOS and anovulatory infertility.