This study has demonstrated that one of the most significant and largest extracellular and intracellular signaling systems, called ERK-1 and ERK-2 kinases, plays a role in PCOS pathogenesis. We observed that heterozygote genotypes of ERK-1 and 2 genes were significantly higher in PCOS and that these polymorphic types were related to some clinical, biochemical and hormonal parameters, such as BMI, FGS, HOMA-IR, and CRP levels. According to the Reference SNP Report (12), the incidence of GA of ERK-1 is generally 1.2–3.4% and the incidence of GC of ERK-2 is 7–8%, or 15–18% in Korea. In our study, the incidences of GA of ERK-1 and GC of ERK-2 were 19.6% and 21.6%, respectively (13). The incidence rates found in our study, which are high compared to other populations, may be unique to Turkey, as our study is the first study to conduct SNP analyses of ERK-1 and ERK-2 genes in the Turkish population. Comprehensive studies conducted by Rivas et al. (12) and Ellegren et al. (14) found results showing that the same genes have different frequencies of polymorphism in different populations, which might explain this high rate of difference.
In one in vivo study, it was shown that LH hormone needed ERK-1 and ERK-2 pathways in order to initiate meiosis and to continue the ovulation and luteinization phases in granulosa cell culture, sequentially and without error(15). In another study, it was observed that due to a mutation in ERK-1/2 kinase genes, oocyte maturation was impaired by a complete lack of germinal vesicle breakdown with impaired coronocumulus cell expansion and corpus luteum formation due to a lack of follicle rupture (16). This problem of cell expansion and follicle rupture may be due to anovulation, which partially explains the excessive number of follicles accumulated in the ovaries (17, 18).
In addition to anovulation, increased intraovarian testosterone levels contribute to the clinical picture of PCOS. Nelson-Degrave et al. (19) and Corbould et al. (20) claimed that excessive ovarian androgen production in women with PCOS was secondary to abnormal activation of the ERK signaling pathway. Other publications assert the opposite. For example, in a study of endometrial cancer patients previously diagnosed with PCOS, Lin et al. (21) concluded that higher testosterone levels cause the phosphorylation of the ERK pathway, which results in an increase in its activity. In addition to this phosphorylation, they also observed that testosterone has a carcinogenic effect by. transforming into estrogen with aromatase enzyme after binding to ER-α36, which activates the ERK pathway As aromatase enzyme activity varies from person to person, and as Lin et al.`s study was conducted in vitro, the results are expected to be confirmed by a large number of studies (22). In our study, testosterone levels were significantly higher in the PCOS group, especially in the GC genotype for ERK-2 and the GA genotype for ERK-1. Similar to our study, research by Hu et al. (23) on Chinese women showed that polymorphic variants of ERK-1 and ERK-2 increased the risk of PCOS development. In the same study, they detected that MAPK signaling was activated by the LH receptor and serum testosterone levels were increased if the MAPK kinase inhibitor PD98059 was given to those patients.
Various studies of PCOS demonstrated that an intersection between reproductive dysfunction and metabolic problems indicates the possible role of adipose tissue dysfunction in PCOS pathogenesis (24, 25). Hence, Manneras-Holm et al. ((26) observed aberrant adipose tissue morphology and function in both underweight and overweight patients with PCOS. To better reveal the role of adipose tissue in PCOS pathogenesis, Kokosar et al. (27) investigated whether there was a genetic change in adipose tissue and found a difference in the activity of many gene pathways in PCOS patients, including in the ERK/MAPK signaling system. Although the number of control patients in that study was small, the screening of a large gene family in patients with PCOS suggests that the results are reliable. In our study, we did not directly evaluate adipose tissue but believed that ERK/MAPK kinase polymorphism affected many tissues in the body, including adipose tissue. Thus, in our study, PCOS patients had higher total cholesterol, LDL, and triglyceride levels compared with the control group. We found that the P-GC genotype for ERK-2 had higher total cholesterol, LDL, and triglyceride levels than the C-GG genotype. This irregularity in lipid levels may be related to different ERK-2 gene polymorphisms and increased lipolysis in patients with PCOS.
Many studies in the literature conclude that there is a relationship between PCOS and chronic low-grade inflammation. Although these studies indicate that this relationship is due to increased BMI, insulin resistance, or hyperandrogenemia accompanying PCOS, no clear reason has been revealed (28). In our study, we detected significantly higher CRP levels in the PCOS group compared to the control group, and these CRP levels were positively correlated with total testosterone, HOMA-IR, and BMI levels. We also wished to examine whether there is a correlation between ERK-1 and ERK-2 kinase polymorphic types and other metabolic parameters, and we detected a significant difference between BMI, HOMA-IR, and CRP levels with both ERK heterozygote types. Based on these results, we may say that there is a sensitive and complex relationship between ERK pathways and inflammation, insulin resistance, and hyperandrogenemia.
Like most studies in the literature, ours has limitations and strengths. As the first study in our population to investigate the ERK-1 and ERK-2 polymorphisms and their relationship with other metabolic parameters in patients with PCOS, novelty is the strongest part of our study. The limitations of the study are that we did not evaluate infertility in patients with PCOS, nor did we classify our patients into obese and lean PCOS groups according to BMI. It is known that the SNP of ERK-1/2 on the 3'-UTR does not cause loss of mRNA`s function, as ERK-1/2 on the 3'-UTR is not found in the open reading frame. Although this may first appear to be a limitation, 3'-UTR mutations affect the half-life of the mRNA by causing mRNA instability, which may ultimately reduce both the function and amount of the end protein product. The presence of fewer ERK-1 and ERK-2 kinase protein in the cell will cause irregularity in the metabolic pathways they control.