This study was conducted to determine the relationship between breast cancer and the clinical symptoms of polycystic ovary syndrome. The results of the present study showed a significant increase of almost 3.7 times in the history of polycystic ovary syndrome and the chance of developing breast cancer. Other researchers have also estimated the risk of breast cancer in women with PCOS from 1.99 to almost 3 times that of the non-afflicted population (7, 25). It seems that women with polycystic ovary syndrome have several risk factors for breast cancer, including hyperandrogenism, oligomenorrhea, amenorrhea, obesity, and infertility (6); however, some studies have not confirmed the relationship between polycystic ovary syndrome and increased risk of breast cancer (5, 26, 27). The results of Mendelian randomization studies showed that in women with polycystic ovary syndrome, there is an increased risk of breast cancer subgroups with estrogen receptor-positive, and probably hyperandrogenism and insulin resistance play the main role in this relationship (24, 29). Wen et al. (2021) also found that the genetic predisposition of polycystic ovary syndrome is associated with an increase in the overall risk of breast cancer; in fact, PCOS only increases the risk of developing a type of breast cancer that has estrogen receptor-positive cells (30). Cao et al. (2023) believe that menopause is probably the mediator between breast cancer and positive estrogen receptors caused by PCOS (4). Regarding the relationship between PCOS and the risk of breast cancer, some aspects of the genetic background can be mentioned. It seems that some genetic pathways known to increase the risk of breast cancer are closely related to the genetic pathways that put a person at risk of polycystic ovary syndrome (31). There is also a hypothesis about the overlap between the gene dysregulation observed in patients with PCOS and genes related to breast cancer, Xu et al. (2017) identified three candidate genes in this regard (32). This relationship existed even in women who only reported a family history of breast cancer, which means that in women with a family history of breast cancer, the history of PCOS was also significantly higher (33). Also, in the study of Soran et al. (2005), the family history of breast cancer was significantly higher in women with PCOS (34). In a long-term follow-up of 786 women with PCOS, breast cancer was the most common cause of death in these women (35).
Other results of the present study showed that among the clinical symptoms of polycystic ovary syndrome, women who had a history of hirsutism had a higher chance (2.188 times) of developing breast cancer than women without a history of hirsutism. It seems that ovarian hyperandrogenism is associated with an increased risk of breast cancer in premenopausal women (36) and among sex hormones, estrogens, their active metabolites, and circulating androgens have a positive relationship with the risk of breast cancer in premenopausal women, and these hormones are more common in patients with polycystic ovary syndrome (37). Researchers have found that disorders related to androgen status, such as a history of hirsutism, acne, and polycystic ovaries, are associated with an increased risk of breast cancer (38).
In the present study, women with breast cancer had a higher history of infertility treatment than the healthy group. Considering that polycystic ovary syndrome is the main cause of infertility worldwide (39), it can be said that the history of infertility treatment in women with PCOS can play an important role in increasing the risk of breast cancer. Naghizadeh et al. (2023) showed that infertility and its treatments can play a role in increasing the risk of breast cancer (40). Farland et al. (2023) also believe that women with a history of infertility are at an increased risk of breast cancer after menopause, and a high age at the time of first delivery and a lower number of parity probably play the main role in this relationship (41). Stentz et al. (2020) found that the risk of death from cancer in infertile women was higher than that in fertile women, whereas the risk of death from breast cancer in infertile women increased more than twice (42).
Another important aspect to consider is the relationship between PCOS, oral contraception use, and breast cancer. In the present study, the studied groups did not have statistically significant differences in terms of the use of hormonal contraceptive methods, and it can be said that it was not associated with an increase in the risk of breast cancer. Conflicting findings exist regarding the relationship between the use of this oral contraceptive and breast cancer. Park et al. (2021) showed that the continuous use of hormonal contraceptives is significantly associated with an increased risk of breast cancer (23). according to the results of Hultstrand et al. (2022), the risk of breast cancer among current users of any combination of hormonal contraceptives was not higher than that among those who never used it (43). Likewise, based on the results of Nagykálnai et al. (2018), while the risk increased with a longer duration of use, the absolute increase was very slight (44).
One of the strengths of the present study was the matching of the two study groups in terms of age and body mass index. High BMI, a common feature of PCOS, is considered an important risk factor for breast cancer. In conclusion, high BMI can both mediate and confound the relationship between PCOS and breast cancer. It appears that the present study is the first case-control study that was controlled in terms of body mass index.
One of the limitations of the present study was that due to the retrospective nature of the study, it was not possible to examine the history of biochemical hyperandrogenism, which is one of the diagnostic criteria of Rotterdam. Therefore, the researchers suggest considering this criterion in future studies if there are suitable conditions