Methods to Test Lifestyle, Vaginal Microenvironment, and Genitourinary Symptoms across Menopause Transition

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Over 50% of postmenopausal women are affected by the genitourinary syndrome of menopause (GSM), which includes vaginal atrophy, vaginal dryness, and sexual dysfunction. Symptoms worsen if untreated and are associated with stress and depression. Estrogen decline in menopause is thought to lead to reduced glycogen accumulation in the vaginal epithelium and is associated with low vaginal Lactobacillus spp. levels in 50-80% of women. Lactobacillus spp. protect the urogenital tract from pathogens in part by producing lactic acid and for their anti-inflammatory properties, but whether lactobacilli are a marker for estrogen levels or play a functional role in GSM is unknown. Available treatments for vulvovaginal GSM symptoms have limitations. Some women are contraindicated for hormonal therapy or are concerned with side effects. Vaginal lubricants provide some relief, but they may be toxic to the vaginal epithelium, reduce lactobacilli, and raise urogenital infection risk. New therapies are needed. Vaginal microbiota are a plausible approach to treatment, however, probiotics alone have not proven effective. Vaginal microbiota co-vary with metabolite and immune profiles, and it is unknown how these molecular features relate to GSM. We hypothesize that core vaginal microenvironment biomarkers (VMB; e.g., microbial, metabolite, and immune profiles) reflect vaginal biological aging (V-BA) that is increased by menopause but may also be modifiable by other factors, such as lifestyle. Longitudinal studies are needed to identify core age-related VMB and determine how they relate to GSM. To accomplish this task, we will develop new statistical methods to combine complex longitudinal epidemiologic data with high- dimensional compositional data. We will leverage 2,301 archived cervicovaginal samples collected as part of a cohort of 812 women aged 35-60 years with visits every six months for two years (R01-CA123467). Specific Aims are to 1) quantify V-BA using VMB; 2) evaluate the longitudinal relationship between V-BA and GSM; 3) longitudinally assess the relationship of lifestyle factors on V-BA and VMB; 4) quantify longitudinal mediation by V-BA and VMB between lifestyle and GSM. Microbiota are already profiled by 16S rRNA gene amplicon sequencing (R21-AI107224). Along with clinical, demographic, and behavioral surveys, we will 1) use cervical secretions and multiplexed bead-based immune-assays to quantify concentrations of 70 immune markers (cytokines, chemokines, growth factors); 2) profile metabolites from vaginal swabs (GC/LC-MS). This proposal is focused on developing and validating new statistical methods that refine and adapt modern structural modeling and microbiota compositional analyses. The novel statistical approaches will allow identification of vaginal microenvironment features which may lead to development of new and effective GSM treatments. These methods will also provide a new framework to handle missing data and confounding that has limited prior microbiome studies. Our team has the multidisciplinary expertise in biostatistics, epidemiology, aging, gynecology, genomics, microbiology, and immunology required for a new systems-biology approach to GSM.