Elsevier

Steroids

Volume 78, Issue 8, August 2013, Pages 782-785
Steroids

Cancer risk and PCOS

https://doi.org/10.1016/j.steroids.2013.04.004Get rights and content

Highlights

  • Women with PCOS have a 2.7-fold increased risk of developing endometrial cancer.

  • Endometrial cancer risk is reduced 50–70% by 4–12 years of oral contraceptive use.

  • A subgroup of PCOS women may be at increased risk of developing ovarian cancer.

  • PCOS women are not more likely to develop breast cancer, controlling for obesity.

  • There are insufficient data to link PCOS with vaginal, vulvar and cervical cancer.

Abstract

Women with polycystic ovary syndrome (PCOS) have a 2.7-fold increased risk for developing endometrial cancer. A major factor for this increased malignancy risk is prolonged exposure of the endometrium to unopposed estrogen that results from anovulation. Additionally, secretory endometrium of some women with PCOS undergoing ovulation induction or receiving exogenous progestin exhibits progesterone resistance accompanied by dysregulation of gene expression controlling steroid action and cell proliferation. Endometrial surveillance includes transvaginal ultrasound and/or endometrial biopsy to assess thickened endometrium, prolonged amenorrhea, unopposed estrogen exposure or abnormal vaginal bleeding. Medical management for abnormal vaginal bleeding or endometrial hyperplasia consists of estrogen-progestin oral contraceptives, cyclic or continuous progestins or a levonorgestrel-releasing (Mirena) intrauterine device. Lifestyle modification with caloric restriction and exercise is appropriate to treat obesity as a concomitant risk factor for developing endometrial disease. An increased risk of ovarian cancer may also exist in some women with PCOS. There are strong data to suggest that oral contraceptive use is protective against ovarian cancer and increases with the duration of therapy. The mechanism of this protection may be through suppression of gonadotropin secretion rather than the prevention of “incessant ovulation”. There is no apparent association of PCOS with breast cancer, although the high prevalence of metabolic dysfunction from obesity is a common denominator for both conditions. Recent data suggest that the use of metformin may be protective for both endometrial and breast cancer. There are insufficient data to evaluate any association between PCOS and vaginal, vulvar and cervical cancer or uterine leiomyosarcoma.

Introduction

Endometrial cancer is the most common reproductive malignancy in women, with more than 40,000 cases diagnosed annually in the United States [1]. Ninety percent of endometrial cancers have an indolent Type I endometroid (estrogen-dependent) pattern, while the remaining 10% are either more aggressive Type II serous/clear cell tumors, or rare but virulent carcinosarcomas [2]. Most women with endometrial carcinoma of the indolent Type I form experience symptomatic vaginal bleeding or discharge that facilitates early diagnosis and treatment. As a result, 72% of women with endometrial cancer are diagnosed with Stage I disease, with the remaining individuals having more advanced disease [3]. This makes endometrial cancer the eighth leading cause of female cancer-related death and responsible for over 7000 deaths annually [1].

Complex interrelationships between endometrial cancer and polycystic ovary syndrome (PCOS) and been recognized for several years and involve multiple risk factors, including obesity, diabetes, hypertension, anovulation, nulliparity and family history [4], [5]. From the first reference of an association between endometrial cancer and PCOS published in 1949 [6], only 14 years after the first classical description of PCOS by Stein and Leventhal [7], several studies have confirmed such an association.[8], [5]. Many of these studies, however, have been retrospective in nature and have relied upon limited data, small numbers of case, various control groups and different PCOS definitions.

More recently, a meta-analysis of four case-control studies comprising 4056 women has estimated the risk of women with PCOS developing endometrial cancer compared to the general population [9]. In this study, the odds of developing endometrial cancer was almost three times higher (OR 2.70, 95% CI 1.00–7.29) in women with PCOS compared to controls, which increased the predicted risk of developing endometrial cancer from 17 per 100,000 women in the general population to 46 per 100,000 women in PCOS women. A subsequent meta-analysis of the same case-control cohort, plus an additional cross-sectional study, confirmed this higher risk of developing endometrial cancer in women with PCOS compared to controls (OR 2.89, 95% CI 1.52–5.48) [10]. These data translate into a 9% lifetime risk of developing endometrial cancer in PCOS vs. 3% in the general population. An Australia-wide, population-based, case-control study of endometrial cancer and PCOS (156 cases; 398 controls) has further shown that women with PCOS less than 50 years of age have a 4-fold increased risk of developing endometrial cancer compared to controls (OR 4.0, 95% CI 1.7–9.3) [11]. Importantly, this increased endometrial cancer risk related to PCOS is reduced by almost one-half when adjusted for body mass index (BMI) (OR 2.2, 95% CI 0.9–5.7), emphasizing obesity as a confounding risk factor for developing endometrial cancer [12]. Consequently, the ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop recently has concluded that there are moderate-quality data to support the premise that women with PCOS have a 2.7-fold increased risk for developing endometrial cancer, most of which are well-differentiated tumors with a good prognosis [13].

Section snippets

Mechanisms of action

Polycystic ovary syndrome and endometrial cancer risk share as a common denominator anovulation, with prolonged endometrial exposure to unopposed estrogen in the absence of sufficient progesterone [14]. In this regard, intermenstrual cycle length positively correlates with risk of developing endometrial hyperplasia [15]. Endometrial responsiveness to progesterone also is inherently different in PCOS women. Secretory endometrium of some women with PCOS receiving ovulation induction or exogenous

Surveillance

In a recent study of 117 women with PCOS by Rotterdam criteria, endometrial thickness and age were significant predictors of endometrial disease [36]. In this study, simple, complex hyperplasia (with or without cytologic atypia) and adenocarcinoma were defined as endometrial disease due to relatively small numbers of cases (simple [12.8%], complex hyperplasia without [5.1%] and with atypia [3.4%], adenocarcinoma [1.7%]). Endometrial thickness of greater than 8.5 mm had a 77.8% sensitivity and

Treatment

Abnormal vaginal bleeding from endometrial hyperplasia is usually associated with thickened, fragile endometrial tissue, resulting from endometrial proliferation due to estrogen action unopposed by progesterone [24]. Therefore, estrogen-progestin oral contraceptives, cyclic or continuous progestogens (medroxyprogesterone acetate 5–10 mg/day, norethindrone acetate 2.5–10 mg/day, micronized progesterone 200 mg/2–3 times daily) or a levonorgestrel-releasing (Mirena) intrauterine device can be used to

Ovarian cancer

Contradictory evidence exists regarding PCOS and risk of ovarian cancer [42], [43]. In a long-term United Kingdom study of 786 women diagnosed with PCOS between 1930 and 1979 through hospital records, and followed for an average of 30 years, mortality from ovarian cancer was not increased compared with the general population (standardized mortality ratio, 0.39; 95% CI 0.01–2.17) [44]. Conversely, a case-control study of women 20–54 years of age with histologically-confirmed epithelial ovarian

Breast cancer

A recent meta-analysis of three studies has analyzed data from 23,842 women (11,836 breast cancer cases and 12,006 controls, of which 59 and 74 had PCOS, respectively) [9]. Data were heterogeneous because individual studies showed either a trend to increased risk, a protective effect, or no risk at all. The collective data, however, showed that women with PCOS were not more likely to develop breast cancer (OR 0.88, 95% CI 0.44–1.77) so that the predicted rates of breast cancer in women with

Other cancers

There is insufficient evidence to evaluate any association between PCOS and vaginal, vulvar and cervical cancer or uterine leiomyosarcoma [9], [13]. Likewise, there are no studies that examine a possible association between PCOS and pre-invasive lesions, such as cervical or vulvar intraepithelial neoplasia.

Conclusions

Women with PCOS have a 2.7-fold increased risk for developing endometrial cancer, most of which are well-differentiated tumors with a good prognosis. The link between PCOS and endometrial cancer involves prolonged endometrial exposure to unopposed estrogen due to anovulation, and endometrial progesterone resistance accompanied by several gene abnormalities controlling progesterone action and cell proliferation. Transvaginal ultrasound or endometrial biopsy is recommended for women with PCOS who

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    Presented at a meeting: 10th Annual Meeting of the Androgen Excess and Polycystic Ovary Syndrome Society, Beijing, Peoples Republic of China, September 21–23, 2012.

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