Introduction
Women experiencing early age at menarche (AAM) are very common(1),(2),(3). Early AAM increases the risk of onset of various diseases, including metabolic disorders(4), cardiovascular diseases(5, 6), autoimmune diseases(7, 8), gynecological diseases and tumors. Also, it is related to subsequent reproductive events in reproductive females, such as gestational diabetes mellitus (GDM)(9), ectopic pregnancies and spontaneous miscarriages(10). Early AAM may even affect the health of her offspring: Early menarche was associated with an increased prevalence of preterm birth (PTB)(11) and low birth weight (LBW) of newborns (12), while PTB and LBW are the risk factors for the rate of infant incidence and mortality.
Previous studies have shown that early AAM can lead to premature hormone exposure and obesity(13), thus risk for various diseases, such as metabolic disorders, cardiovascular diseases, gynecological diseases and tumors. Both of premature hormone exposure and pre-pregnancy obesity affect immune functions(14, 15). In recent years, some studies found that early AAM was associated immune-related conditions, such as systemic lupus erythematosus (SLE) and asthma: early AAM and hormone treatments were risk factors for the onset of SLE(8). Also, a new phenotype for asthma has been discovered among the female population—the earlier the AAM, the higher the clinical score for asthma(7). In a cross-sectional study, early AAM was found to be associated with the risk of subclinical hypothyroidism(16). It implied that early AAM accompanied by early exposure to estrogen may trigger thyroid autoimmunity, which will further impair the gravidas and fetuses(17).
Moreover, the subsequent reproductive events associated with AAM are tightly linked to inflammation and immune functions. For example, maternal serum levels of circulating TNF-α, IL-6 and CRP are increased in GDM patients(18). Pelvic inflammation is identified as a risk factor of ectopic pregnancies(19). And uterine immunity are pivotal for successful implantation, and the aberration of immune function is related to spontaneous miscarriages(20). However, the logical connection between early AAM, immune functions and subsequent reproductive performance are scarcely studied. We hypothesized that immunity mediating the process of early AAM-induced pregnancy complications.
To validate this hypothesis, we firstly analyzed the association of pre-pregnancy immune functions with AAM and reproductive events by using flow cytometry in this study. Then we validated the causal relationship between AAM and immune function by two sample Mendelian Randomization (MR) test using public Genome-wide association (GWAS) data. Our reports are herein.