**6. Poly cystic ovarian syndrome and cancers**

Since 1940s, there is emerging evidence of increased risk of gynecological cancer including endometrial, breast and ovary cancer among women with PCOS [71, 72]. Any association with malignant disease would be highly important from a public health perspective in view of the high prevalence of PCOS. The lack of appropriate recognition of risks takes these patients at highest risk of delayed diagnosis of pre-malignant or malignant disease [70]. At a cellular level there are numerous potential mechanisms which could promote neoplastic disease in women with PCOS, including the prolonged anovulatory state and associated hyperandrogenism with unopposed estrogen action [73]. These could increase the risk of cancer through the effect of these hormones on various tissue and organs [74].

#### **6.1. Endometrial carcinoma and PCOS**

Endometrial carcinoma (EC) is the second most frequent gynecological malignancy among women [74]. The number of reported cases of EC makes it the leading cause of cancer-related deaths across the globe [75]. Major EC-related symptoms include dysfunctional uterine bleeding, hyper-menorrhea, irregular menstruation, and sterility. The two main types of EC are estrogen-dependent type I (the most prevalent type) and estrogen-independent type II carcinomas. Among numerous risk factors, PCOS is commonly considered to be a significant and causative risk factor for the development and progression of type I EC [76]. The prevalence of endometrial hyperplasia with and without atypia in women with PCOS varies from 1 to 48.8% [77]. The prevalence of EC is three times higher among women with PCOS than among women without PCOS [71]. The mechanisms underlying EC and PCOS are also unclear, but it is widely assumed that chronic anovulation, which results in continuous estrogen stimula‐ tion of the endometrium unopposed by progesterone, is a major factor. Obesity, hyperinsuli‐ nemia, and hyperandrogenism state in PCOS, results in increased bioavailability of unopposed estrogens by progesterone due to the increased peripheral conversion of endogenous andro‐ gens such as testosterone and androstenedione into estrogen. Also, Insulin up-regulates aromatase activity in endometrial glands and stroma, endogenous estrogen production is enhanced in women with high circulating insulin. Estrogens act as proliferative factors in the endometrial tissue. Continuous exposure of the endometrium to estrogens with persistent progesterone deficiency, lead to endometrial overgrowth and hyperplasia or cancer [78]. The exact molecular mechanisms linking hyperinsulinaemia as found in PCOS and EC are uncertain. It is however thought that it may be modulated by a direct effect of insulin and IGF on endometrial cells or alterations in the P13K-mTOR-AKT signaling pathway with the loss of PTEN expression which have mitogenic effect on endometrial cells [79] and activation of insulin/IGF-1 signaling through overexpression of INSR and/or IGF-1R.

Overlay, the evidences suggest that interplay between hyperinsulinaemia and estrogen may mediate the mitogenic effect of the hyperinsulinaemia in PCOS.

Other potential risk factors for EC such as androgens and LH are also present in PCOS. Hypersecretion of luteinising hormone, a feature of PCOS, has also been implicated in the develop‐ ment of endometrial cancer in women with PCOS. Receptors for luteinising hormone and human chorionic gonadotropin are over expressed at both mRNA and protein levels in endometrial adenocarcinomas. Over expression of receptors for both these hormones in endometrial hyperplasia (with stronger staining in complex or atypical hyperplasia), and endometrial carcinoma were detected [80]. Insulin levels reduce the amount of IGFBP which in turn increases the amount of circulating IGF. IGF has been shown to induce LH receptors increasing LH levels, again suggesting an interaction between insulin resistance, LH and EC [81]. It should be noted that the triad of obesity, insulin resistance and diabetes in metabolic syndrome carried significant risks of EC [82]. However, the evidence for impact of PCOS on prognosis of endometrial carcinoma is incomplete and contradictory. Jafari et al. suggested that the presence of PCOS was associated with a favorable prognosis [83]. Insulin has also been found to accelerate the proliferation of cancer cell in the endometrium in an in-vitro study [82], and the concentration of IGF-1 was correlated well to the malignant cells differentiation [79], but, There is not enough knowledge supporting that mortality from endometrial cancer is differ in women with the syndrome.

However, it has been clearly shown in both animal and human studies that *metformin* is valuable insulin sensitizer agent in reversing endometrial hyperplasia. Metformin has exerted a chemo-protective and anti-proliferative effect on EC. It does this by a reduction in cell growth, which is modulated partly via insulin and non-insulin relevant path-ways. In the context of the links between EC and hyperproloferation of endometrium in PCOS, Metformin may therefore prevent EC in PCOS or treatment of EC.

#### **6.2. Ovarian carcinoma and PCOS**

**6. Poly cystic ovarian syndrome and cancers**

these hormones on various tissue and organs [74].

**6.1. Endometrial carcinoma and PCOS**

86 Contemporary Gynecologic Practice

Since 1940s, there is emerging evidence of increased risk of gynecological cancer including endometrial, breast and ovary cancer among women with PCOS [71, 72]. Any association with malignant disease would be highly important from a public health perspective in view of the high prevalence of PCOS. The lack of appropriate recognition of risks takes these patients at highest risk of delayed diagnosis of pre-malignant or malignant disease [70]. At a cellular level there are numerous potential mechanisms which could promote neoplastic disease in women with PCOS, including the prolonged anovulatory state and associated hyperandrogenism with unopposed estrogen action [73]. These could increase the risk of cancer through the effect of

Endometrial carcinoma (EC) is the second most frequent gynecological malignancy among women [74]. The number of reported cases of EC makes it the leading cause of cancer-related deaths across the globe [75]. Major EC-related symptoms include dysfunctional uterine bleeding, hyper-menorrhea, irregular menstruation, and sterility. The two main types of EC are estrogen-dependent type I (the most prevalent type) and estrogen-independent type II carcinomas. Among numerous risk factors, PCOS is commonly considered to be a significant and causative risk factor for the development and progression of type I EC [76]. The prevalence of endometrial hyperplasia with and without atypia in women with PCOS varies from 1 to 48.8% [77]. The prevalence of EC is three times higher among women with PCOS than among women without PCOS [71]. The mechanisms underlying EC and PCOS are also unclear, but it is widely assumed that chronic anovulation, which results in continuous estrogen stimula‐ tion of the endometrium unopposed by progesterone, is a major factor. Obesity, hyperinsuli‐ nemia, and hyperandrogenism state in PCOS, results in increased bioavailability of unopposed estrogens by progesterone due to the increased peripheral conversion of endogenous andro‐ gens such as testosterone and androstenedione into estrogen. Also, Insulin up-regulates aromatase activity in endometrial glands and stroma, endogenous estrogen production is enhanced in women with high circulating insulin. Estrogens act as proliferative factors in the endometrial tissue. Continuous exposure of the endometrium to estrogens with persistent progesterone deficiency, lead to endometrial overgrowth and hyperplasia or cancer [78]. The exact molecular mechanisms linking hyperinsulinaemia as found in PCOS and EC are uncertain. It is however thought that it may be modulated by a direct effect of insulin and IGF on endometrial cells or alterations in the P13K-mTOR-AKT signaling pathway with the loss of PTEN expression which have mitogenic effect on endometrial cells [79] and activation of

insulin/IGF-1 signaling through overexpression of INSR and/or IGF-1R.

mediate the mitogenic effect of the hyperinsulinaemia in PCOS.

Overlay, the evidences suggest that interplay between hyperinsulinaemia and estrogen may

Other potential risk factors for EC such as androgens and LH are also present in PCOS. Hypersecretion of luteinising hormone, a feature of PCOS, has also been implicated in the develop‐ ment of endometrial cancer in women with PCOS. Receptors for luteinising hormone and Ovarian cancer accounts for 5% of all cancers among women and is the fourth most common cause of cancer deaths in developed countries, causing more deaths than any other female genital tract cancer [84]. Ovarian cancer typically presents late, with symptoms such as pelvic pain, abnormal vaginal bleeding, or involuntary weight loss, and has an overall 5-year survival of 30% after diagnosis. However, if detected early, at stage I, the 5-year survival is as high as 90%. It is, therefore, imperative that high-risk groups are identified so that appropriate screening is undertaken to detect early ovarian malignancy [85].

The majority of malignant ovarian tumors including epithelial malignancies appear to have steroid receptors for estrogen, progesterone and androgen. Cytokines may also play a role in malignant transformation. The various interactions of altered local ovarian factors and environmental factors have been associated with OC, as many of these factors are altered in PCOS.

Epidemiology studies showed that women with PCOS had a 2.5-fold increased risk of developing ovarian cancer, with a 95% confidence interval of 1.1–5.9 [86]. Also, clomiphene citrate and gonadotropin therapy or ovulation induction was found to increase the relative risk of ovarian tumors in women with PCOS around 4.1 [87]. The pathophysiological mecha‐ nisms that may be involved in ovarian oncogenesis in women with PCOS are not completely understood. Perhaps the high local steroid and growth factor concentrations that are frequent‐ ly observed in women with PCOS may be implicated [88]. In addition, ovulation inducing drugs potentially which are used for infertility treatment, may have effect on ovarian cancer [89]. Some researchers suggest that oral contraceptive use in some anovulatory women with PCOS may protect against ovarian cancer through gonadotropin suppression rather than the prevention of ''incessant ovulation'', with its putative dangers of inclusion cyst formation, epithelial proliferation, genetic damage and ovarian carcinogenesis [89].

#### **6.3. Breast cancer and PCOS**

Obesity, hyperandrogenism and infertility occur frequently in PCOS, and are feature known to be associated with the development of breast carcinoma [89]. In this respect, meta analysis about the association between PCOS and breast cancer showed that the risk of breast cancer was not significantly increased overall [90]. However, some studies showed that women with PCOS independently of age, age at menarche or menopause, parity, using oral contraceptive pill, BMI and family history of breast cancer, have 1.8 times as likely to report benign breast disease [91]. In this regard there is a need for more research.
