Effects of FSHR polymorphisms on premature ovarian insufficiency in human beings: a meta-analysis

Premature ovarian insufficiency (POI) is currently defined as apparent deterioration of ovarian function before the age of 40 in human beings [1]. It is characterized by an elevated level of follicle-stimulating hormone (FSH), a decreased level of estrogen, oligomenorrhea or amenorrhoea as well as an increased risk of osteoporosis and multiple cardiovascular diseases [2]. According to a recent epidemiological study, the prevalence of POI is estimated to be around 1% in women younger than 40 years old [3]. To date, the exact pathogenic mechanism of POI is still largely unknown. Nevertheless, there is mounting evidence to support that genetic factors play vital roles in its occurrence and development. First, family aggregation of POI in human beings is not uncommon, and it is estimated that about 10–30% of POI patients have positive family history [4]. Second, various genetic variants have already been found to be correlated with an increased risk of POI in human beings by previous experimental studies [5, 6]. In summary, these findings jointly indicated that genetic predisposition to POI is crucial for its development.

FSH is a glycoprotein secreted by the pituitary gland, and it plays a crucial role in promoting follicle growth and regulating ovarian function by acting on the FSH receptor (FSHR) [7]. Therefore, it is biologically plausible that functional FSHR polymorphisms may result in dysfunction of FSH, lead to decreased ovarian function and give rise to the development of POI in human beings. The rs6165 and rs6166 polymorphisms are two commonly seen missense mutations of FSHR, the G to A transvertion at these two loci lead to amino acid residue substitution of the corresponding amino acid sequence, and thus these two polymorphisms may affect bonding of FSH and FSHR [8]. Previous studies have shown that rs6165 and rs6166 polymorphisms were actually correlated with a higher serum FSH level and reduced FSH efficiency in human beings [9, 10]. Considering the functional significances of rs6165 and rs6166 polymorphisms, several pilot studies have already been conducted to investigate the possible correlation between these two polymorphisms and POI. However, the results of these studies were inconsistent and the sample size of individual studies was relatively small. Therefore, we conducted this meta-analysis to better analyze the roles of FSHR polymorphisms in POI.

There are several points that need to be addressed about this meta-analysis. Firstly, no obvious heterogeneities were detected in overall analyses for two investigated polymorphisms, which indicated that eligible studies could be considered as homogeneous, and thus synthesize the results of these studies is statistically feasible. Secondly, the pathogenic mechanism of POI is highly complex, and hence it is unlikely that a single gene polymorphism can significantly contribute to its development. Therefore, to better illustrate potential correlations of certain gene polymorphisms with POI, we strongly recommend further studies to perform haplotype analyses and explore potential gene-gene interactions.

As with all meta-analysis, this study certainly has some limitations. First, our findings were based on unadjusted estimations due to lack of raw data, and failure to conduct further adjusted analyses for age, gender and co-morbidity conditions may impact the reliability of our findings [13, 14]. Second, association between FSHR polymorphisms and POI may also be influenced by gene-gene and gene-environmental interactions. However, the majority of studies did not consider these potential interactions, which impeded us to perform relevant analyses accordingly [15]. Third, only retrospective case-control studies were included in this meta-analysis, and thus direct causal relation between FSHR polymorphisms and POI could not be established. Taken these limitations into consideration, the results of the current study should be interpreted with caution.

Overall, our meta-analysis suggests that the FSHR rs6166 polymorphism may serve as a potential genetic biomarker of POI in Asians, but not in other ethnicities. However, further well-designed studies with larger sample sizes are warranted to confirm our findings. Additionally, future investigations are needed to explore the potential roles of other FSHR polymorphisms in the development of POI.