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.