Metabolomic signatures of reproductive stages: a longitudinal study

Abstract

Menopause is linked to declining levels of estrogen, loss of protective vaginal lactobacilli, and age-related comorbidities, including the Genitourinary Syndrome of Menopause (GSM). GSM covers a wide range of symptoms, including genital dryness, irritation, discomfort or pain, urinary urgency, and recurrent urinary tract infections. Vaginal metabolites reflect the metabolic activity of the microbiota and human host, along with exogenous influences, and can modify susceptibility to multiple pathologies. To date, very few studies exist that have focused on the vaginal metabolome of post-menopausal participants. To address these gaps, we sought to characterize the vaginal metabolome across reproductive stages. 476 participants (aged 35-60 years) contributed semiannual in-person visits over two years (N=1,153 samples). Bayesian mixed-effects regression of log2-transformed metabolites (n=770) assessed metabolomic differences in samples from pre- (n=287), peri- (n=335), and post-menopausal (n=531) participants, 25% of whom were racial/ethnic minorities. Samples collected from post-menopausal participants had distinct metabolomic profiles compared to pre- or peri-menopausal samples (543 metabolites were lower in post-menopausal samples; p<0.05). Metabolites reflecting epithelial damage and oxidative stress, along with host-produced lysophospholipids (e.g., lactosyl-N-palmitoyl-sphingosine), were highest in samples from post-menopausal participants (p<0.05). Further investigations linking menopause and race/ethnicity with oxidative stress-related metabolites are needed to reduce disparities in healthy reproductive aging.