In this study, we applied MR and bioinformatics method to investigate the causal relationship and biological mechanisms between birth weight, childhood obesity and age at menarche and ovarian function. The results showed that childhood obesity increased the risk of ovarian dysfunction in females (OR = 1.378, 95% CI: 1.113–1.705, P = 0.003), and the later the age at menarche, the lower the risk of ovarian dysfunction (OR = 0.639, 95% CI: 0.468–0.871, P = 0.005) and primary ovarian failure (OR = 0.510, 95% CI: 0.283–0.918, P = 0.025). This may be related to lipid and parathyroid hormone synthesis and secretion processes, and there was no causal relationship between birth weight and ovarian dysfunction and primary ovarian failure.
Due to the original ovarian follicle pool being established within the uterus, it may be influenced by parental characteristics and the intrauterine environment [25]. Additionally, a study in 2007 [26] suggested that newborns with relatively lower birth weights have smaller ovarian volumes, raising the hypothesis that smaller ovarian volume and ovarian dysfunction in females may originate during fetal development. However, a study in 2011 found no significant differences in follicular-phase LH, FSH, AMH levels, or the response to endogenous GnRH between small for gestational age and appropriate for gestational age females [27]. This suggests that there may be no correlation between female ovarian function and birth weight. The contrasting results between these two studies could be attributed to the challenges of conducting extensive clinical follow-ups, resulting in limited sample sizes and potential biases influenced by various confounding factors. Our study found that birth weight, although not causally associated with ovarian function, resulted in elevated E2 levels. This is consistent with the findings of a previous study [28] that neonates with relatively low birth weight have more pronounced activation of the hypothalamic-pituitary-gonadal axis and relatively higher E2 levels than term infants, but genetically this does not have an impact on ovarian function.
A study conducted in 2014, which included 103 participants, found a higher prevalence of ovarian dysfunction among females who had insufficient weight during childhood [29]. Recent research has consistently indicated that childhood obesity leads to an earlier onset of puberty in females, increases the risk of developing polycystic ovary syndrome in adulthood, and affects fertility, among other factors [30, 31]. However, studies exploring the relationship between childhood obesity and adult ovarian function have been lacking. Inconsistent with previous studies, our study found that women who were obese in childhood had a higher risk of ovarian dysfunction, which may be related to the coordinated action of various hormones such as leptin, insulin, and epinephrine [32]. Leptin receptors are present in the hypothalamus and anterior pituitary gland in gonadotrophoblasts, ovarian follicular cells, and mesenchymal stromal cells, which accelerate the pulsation of gonadotropin-releasing hormone (GnRH) that leading to increased gonadotropin secretion and gonadal maturation, and in obese individuals, inhibitory effects on the gonads due to the presence of leptin resistance [33]. For example, rs9941349 is located in the intron of the FTO gene, and it has been found that FTO abnormalities are associated with oocyte maturation disorders and premature ovarian failure, but the exact mechanism still needs to be elucidated in subsequent studies [34].
The earliest study in 2012 [35] found that women with earlier menarche had higher AMH levels at a younger age, higher numbers of follicles in the ovaries, and better ovarian reserve function, but failed to conduct a study of longer duration. On the contrary, a 2013 study by Andrea Weghofer et al [36] showed that the earlier the age at menarche, the greater the risk of ovarian hypoplasia, which may be related to the size of the follicular pool and/or the rate of follicular recruitment. 2018 and 2021 studies [37, 38], however, found no correlation between the age at menarche and women's ovarian function. Considering that in addition to genetics, menarche is also influenced by socioeconomic and environmental factors, such as race, BMI, geography, nutritional habits, and exercise have been shown to affect age at menarche, there has been controversy as to whether age at menarche is correlated or causally related to ovarian function in females, and it is difficult for observational studies to come up with a definitive answer. Our study confirmed genetically that the later the age at menarche, the lower the risk of ovarian failure. Parathyroid hormone responsive-B1 (PTHB1) gene expression responds to parathyroid hormone, and BBS is a genetically heterogeneous autosomal recessive disorder [39], whose main symptoms are obesity [40] and ovarian hypoplasia [41] showed that PTHB 1 is expressed early in human adipogenesis and has a high correlation with POF, so it is hypothesised that PTHB 1 variants increase the risk of developing POF.
Unlike previous observational studies that were susceptible to confounding factors and the disadvantage that RCT experiments are difficult to carry out in large numbers in the clinic, MR studies minimise the inherent bias due to confounding factors or reverse causality, while combining the functional enrichment and protein-protein interaction network approaches to provide new insights into the specific mechanisms underlying the relationship between childhood obesity, age at menarche and ovarian function. insights. However, there are several limitations of our study. Firstly, the MR analysis could only use the available genetic data and could not exclude other non-genetic factors, such as lifestyle, which may influence the development of the disease; secondly, the data obtained did not have more detailed cohort data, such as age and sex, and could not be further analysed in subgroups; and lastly, the data used in this study was ethnically homogeneous, and it is important to be cautious when extending the results to other populations with different lifestyles and cultural traditions. Finally, the data used in the study were ethnically homogeneous and caution should be exercised when generalising the results to other populations with different lifestyles and cultural traditions.