Risk of endometrial, ovarian, and breast cancers in women with polycystic ovary syndrome: A systematic review and meta-analysis

Abstract Background Although several studies have evaluated the risk of gynecological cancers in women with polycystic ovary syndrome (PCOS), there are controversies regarding it. Objective This study aimed to investigate the association of PCOS with endometrial, ovarian, and breast cancers. Materials and Methods PubMed, Scopus, Web of Science, and Google Scholar databases based on MESH terms using the combination of the appropriate keywords were searched to retrieve observational studies on endometrial, ovarian, and breast cancers in PCOS women, published from inception to April 2020. This meta-analysis was performed to determine the pooled odds ratio (OR) of these cancers in women with PCOS. Publication bias was assessed by using Begg's test. Results Of 1347 records retrieved by searching the databases, a total of 14 articles were included in the study. Overall, the pooled OR of the composite outcome, including endometrial, ovarian, and breast cancers in women with PCOS was higher than that of women with no PCOS (pooled OR: 1.4, 95% CI: 1.0-1.9). The pooled OR of endometrial (pooled OR: 2.2, 95% CI: 1.03-4.7) and ovarian (pooled OR: 1.3, 95% CI: 1.0-1.8) cancers in women with PCOS was higher than the control group, whereas the pooled OR of breast cancer was not significantly higher than that of the control group. Conclusion This meta-analysis indicated an increased risk of endometrial and ovarian cancers in women with PCOS.

The high prevalence of endometrial hyperplasia and carcinoma due to chronic anovulation, associated with prolonged exposure to unopposed estrogen has been long recognized. Moreover, PCOS complications, such as obesity, nulliparity, diabetes, and hypertension, are risk factors for endometrial carcinoma (8)(9)(10). In this regard, a populationbased cohort study reported a 17-fold increase in the risk of endometrial cancer among women with PCOS, compared to those without PCOS (11). Several hypotheses have been proposed for the increased risk of ovarian cancer in PCOS women, such as anovulation, increased androgen exposure, and lack of progesterone (12). Another study found that the risk of ovarian cancer was 2.5 times higher in women with PCOS compared to healthy women (13). It is possible that the sustained elevation of serum estrogen levels may lead to the growth of hormone-sensitive tumors, such as breast cancer (14); therefore, anovulation can be considered as a critical risk factor in women with PCOS. Several studies have investigated the risk of breast cancer in women with PCOS; however, the actual risk remains unclear (11,(15)(16)(17). Although some studies have assessed the risk of endometrial, ovarian, and breast cancers in women with PCOS, their results are often conflicting, and the risk of these cancers in women with PCOS is still debated (11,13,15,16,18).
Hence, this study aims to conduct a metaanalysis of observational studies to investigate the association of PCOS with endometrial, ovarian, and breast cancers. Since the severity of PCOS manifestations can distort the results, we adjusted the results for PCOS diagnostic criteria in a meta-regression analysis.

Materials and Methods
This meta-analysis was designed according to the guidelines for the preferred reporting items for systematic reviews and meta-analyses (PRISMA) to assess the pooled odds ratio of endometrial cancer in women with PCOS, compared to healthy controls (19).

Eligibility criteria
All types of observational studies, including case-control, cross-sectional, and cohort designs were eligible to be included in the meta-analysis.
Studies needed to report raw data of events, odds ratio (OR), and relative risk to provide sufficient information to allow calculation. Any PCOS diagnosis criteria were eligible to be included, for example, Rotterdam, National Institute of Health, Androgen Excess Society, International Classification of Diseases, and also a self-reported questionnaire.
The exclusion criteria included studies 1) assessing conditions, for example, polycystic ovary, androgen excess disease instead of PCOS, 2) without control groups, 3) with unreliable and incomplete results, and 4) assessing hyperplasia rather than cancer.

Study selection
All relevant studies assessing at least one of the cancers of endometrial, ovarian, and breast in women with PCOS were included in this metaanalysis.
Search results were screened based on the predefined eligibility criteria. All references were entered into EndNote software. The initial selection was based on article titles, and then a second selection based on abstracts was done and duplicates were deleted by one reviewer (A.F). Finally, the full text of selected articles was reviewed for data extraction. Disagreements were resolved by 2 other reviewers (M. A. and F.R.T.).

Bias assessment
Cochrane collaboration's tools were applied to assess the risk of bias in each study (21).

Outcome measures
In this meta-analysis, outcomes of interest were endometrial cancer, ovarian cancer, and breast cancer.

Meta-analysis and meta-regression of outcomes
In this meta-analysis, 12 of meta-regression analysis revealed that the diagnostic criteria of PCOS and age had no significant effects on the heterogeneity of the outcomes ( Figure 6).

Publication bias, risk of bias, and sensitivity analysis
The results of Begg's test showed a significant publication bias for endometrial cancer in both PCOS and non-PCOS groups and breast cancer in the PCOS group, which was adjusted by the trim and fill method (Table IV, Figure 7).   The quality assessment has been evaluated based on the Newcastle-Ottawa scale. A study can be awarded a maximum of one star (*) for each numbered item within the selection and exposure categories. A maximum of 2 stars can be given for comparability, BMI: Body mass index  The quality assessment has been evaluated based on the Newcastle-Ottawa scale. A study can be awarded a maximum of one star (*) for each numbered item within the selection and exposure categories. A maximum of 2 stars can be given for comparability, BMI: body mass index International Journal of Reproductive BioMedicine Amiri et al.

Discussion
This meta-analysis was carried out to assess the association of PCOS with endometrial, ovarian, and breast cancers. The results revealed that PCOS was associated with an increased risk of endometrial and ovarian cancers, but not breast cancer.
It is known that in women with PCOS who have  has been hypothesized to be associated with an increased risk of ovarian cancer (12). This association could be explained by evidence regarding the presence of androgen receptors on healthy ovarian cells, as well as benign and borderline tumors (12). Moreover, it has been shown that higher androgen levels during pregnancy were associated with an increased risk of borderline serous and mucinous tumors (47,48). Hyperinsulinemia and the resulting increase in insulin-like growth factor-1, which plays an important role in tumorigenesis, have also been suggested as the main mechanism (49).
The present study indicates that the risk of  (50). However, obesity is a major risk factor for breast cancer in both post and premenopausal women, and as mentioned previously, it is also a common finding in PCOS women (51). This reduction in the risk of breast cancer among women with ovulatory disorders is because of luteal phase deficiency in the menstrual cycle; therefore, the levels of estrogen and progesterone do not increase.
Also, it is well-documented that breast cancer cell proliferation is higher during the luteal phase (18,52). Moreover, hyperinsulinemia has been suggested as an independent risk factor for breast cancer (53). The correlation between androgen excess and the pathogenesis of PCOS is still controversial; however, androgens seem to trigger the development of estrogen-receptor (ER)-negative breast cancer (54,55). Advanced maternal age during the first pregnancy and nulliparity are also important risk factors for breast cancer (56).
Despite the mentioned mechanisms, we found no significant association between PCOS and breast cancer. Similar to our results, a meta-analysis showed that women with PCOS were not exposed to a higher risk of breast cancer, compared to those without PCOS (14).
Likewise, another meta-analysis of 8 studies found no significant association between PCOS and breast cancer (57). Similarly, a recent metaanalysis reported no significant association between PCOS and breast cancer (45

Conclusion
This study indicated the increased risk of endometrial and ovarian cancers in women with PCOS. Therefore, screening programs for early detection of these cancers, especially in women with PCOS, can be considered an important strategy for improving their survival.