Cancer risk and PCOS☆
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
References (47)
- et al.
Carcinoma of the corpus uteri. FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer
Int J Gynaecol Obstet
(2006) - et al.
Anovulation with or without PCO, hyperandrogenaemia and hyperinsulinaemia as promoters of endometrial and breast cancer
Best Pract Res Clin Obstet Gynaecol
(2010) - et al.
Amenorrhea associated with bilateral polycystic ovaries
Am J Obstet Gynecol
(1935) - et al.
The Stein-Leventhal syndrome: analysis of 43 cases with special reference to association with endometrial carcinoma
Am J Obstet Gynecol
(1957) - et al.
Polycystic ovary syndrome and the risk of gynaecological cancer: a systematic review
Reprod Biomed Online
(2009) - et al.
Endometrial cancer and obesity: epidemiology, biomarkers, prevention and survivorship
Gynecol Oncol
(2009) Progestogen deficiency and endometrial cancer risk
Maturitas
(2009)Ultrasound and menstrual history in predicting endometrial hyperplasia in polycystic ovary syndrome
Obstet Gynecol
(2001)- et al.
Evaluation of steroid receptors, coregulators, and molecules associated with uterine receptivity in secretory endometria from untreated women with polycystic ovary syndrome
Fertil Steril
(2006) - et al.
Increased expression of LH/hCG receptors in endometrial hyperplasia and carcinoma in anovulatory women
Gynecol Oncol
(1997)
Prevalence of insulin resistance in the polycystic ovary syndrome using the homeostasis model assessment
Fertil Steril
The use of hormonal contraception and its protective role against endometrial and ovarian cancer
Best Pract Res Clin Obstet Gynaecol
Epithelial ovarian cancer risk among women with polycystic ovary syndrome
Obstet Gynecol
Mortality of women with polycystic ovary syndrome at long-term follow-up
J Clin Epidemiol
Adipose tissue and breast epithelial cells: a dangerous dynamic duo in breast cancer
Cancer Lett
Cancer statistics, 2005
CA Cancer J Clin
Polycystic ovary syndrome and endometrial cancer
Semin Reprod Med
Carcinoma of the endometrium in young women
Surg Gynecol Obstet
Evaluating the association between endometrial cancer and polycystic ovary syndrome
Hum Reprod
Australian Ovarian Cancer Study Group and Australian National Endometrial Cancer Study Group. Polycystic ovary syndrome increases the risk of endometrial cancer in women aged less than 50 years: an Australian case-control study
Cancer Causes Control
Consensus on women’s health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group
Fertil Steril
Progesterone resistance in PCOS endometrium: a microarray analysis in clomiphene citrate-treated and artificial menstrual cycles
J Clin Endocrinol Metab
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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.