Genetic Aspects of Vaginal Aging

Sponsor
Żelazna Medical Centre, LLC (Other)
Overall Status
Recruiting
CT.gov ID
NCT05318989
Collaborator
Laboratory of Genetics and Human Genomics, University of Gdańsk (Other)
120
1
22.7
5.3

Study Details

Study Description

Brief Summary

Life expectancy depends on a number of different factors, of which only about 20-30% are genetically determined. The overwhelming majority are non-genetic determinants. One of the proposed mechanisms explaining this aging phenomenon is related to epigenome variability. Epigenetic regulation is mainly based on cytosine methylation / demethylation in DNA and modification of histone proteins. DNA methylation, unlike modification of histone proteins, is a permanent change, the effects of which can be very distant, and the methylation patterns are fixed during subsequent cell divisions. This type of epigenetic modification plays an important role in a variety of cellular processes, such as differentiation, transformation and aging. The most commonly methylated are cytosines within two nucleotide sequences in DNA called CpG islands. Numerous studies confirm the age-related reduction in methylcitosine (5-mC) levels in both the nuclear and mitochondrial genome of cells in various tissues. The enzymes that catalyze this process belong to the family of methyltransferases (DNMTs). Cytosine methylation appears to be one of the key processes in tissue aging. Depending on the type of tissue and DNA region, there is an increase or decrease in cytosine methylation with age. The main process of both passive and active demethylation is the hydroxymethylation of methylcytosine leading to the formation of hydroxymethylcytosine (5-hmC). This process is of great importance in the regulation of gene expression. Three hydroxylases, TET 1-3 enzymes (ten-eleven translocation), take part in the 5mC hydroxylation process in mammalian cells. The resulting 5-hmC is an important intermediate in the process of DNA demethylation. The significant decrease in the level of CpG island methylation in the genome also seems to be of key importance. So far, the role of 5mC, and thus the activity of TET enzymes in the aging process, has not been clearly defined. Previous studies have shown that it can play an important role in the development and aging of the body. In a woman's life, the consequences of the aging process are most severely manifested during the menopause. The deficiency of sex hormones determines a number of processes also occurring in the lower urinary tract. Estrogens are an essential regulator of the physiological function of the vagina. 40-60% of postmenopausal women complain of atrophic changes in the vaginal epithelium (VVA - vulvovaginal atrophy). Vaginal topical estrogens are currently the "gold standard" in VVA therapy. The molecular mechanism of action of estrogens is based on their activation of the estrogen receptors ER-alpha and ER-beta located in the nuclear envelope of cells in target organs. After the ligand binds to the appropriate receptor, a cascade of signals activating the appropriate chromatin-binding transcription factors is triggered. As a result of this process, the expression of genes involved in the processes of proliferation, differentiation as well as apoptosis changes. Therefore, local administration of estrogens is the most effective in improving the physiological condition of the vaginal mucosa epithelium. The question arises, how do hormonal deficiencies appearing in the menopausal period affect epigenetic changes in the genome and, consequently, the modification of gene expression related to the aging processes of the organism? Does the use of hormone therapy affect the regulation of gene expression through changes in the level of genome methylation? Can the determination of the level of total methylation in vaginal mucosa cells serve as a marker of the advancement of the aging process? Additionally, will the assessment of the degree of demethylation of the genome of vaginal mucosa cells by analyzing the level of expression of genes encoding TET 1-3 enzymes and the total level of 5mC allow characterizing epigenetic changes occurring in menopausal women? Is it possible to identify specific genes whose methylation-dependent expression regulates aging? Obtaining answers to such questions may contribute to understanding the role of the epigenome in the aging process of cells, and opening up new possibilities for the implementation of more effective therapies. It is also crucial that the vaginal epithelium is generally not exposed to known environmental factors influencing the course of aging (e.g. UV radiation), and thus the observed epigenetic changes in vaginal epithelial cells should reflect the impact of hormonal disorders on the molecular mechanism of aging.

Condition or Disease Intervention/Treatment Phase

    Study Design

    Study Type:
    Observational
    Anticipated Enrollment :
    120 participants
    Observational Model:
    Cohort
    Time Perspective:
    Cross-Sectional
    Official Title:
    Epigenetic Profile of Vaginal Epithelial Cells in Postmenopausal Women and as a Result of Local Hormone Therapy, Assessed on the Basis of the Analysis of DNA Methylation Level and Expression of TET 1-3 Genes in Terms of the Aging Process
    Actual Study Start Date :
    Feb 8, 2021
    Anticipated Primary Completion Date :
    Dec 28, 2022
    Anticipated Study Completion Date :
    Dec 30, 2022

    Arms and Interventions

    Arm Intervention/Treatment
    Premenopausal women (PREM)

    Control group

    Postmenopausal women (POSMA)

    Test group A : postmenopausal women not treated with topical estrogens

    Postmenopausal women (POSMB)

    Test group B: postmenopausal women treated with topical estrogens

    Outcome Measures

    Primary Outcome Measures

    1. 5-hmC content [30 days]

      - 5-hmC content and 5-mC increase in tissues with urogenital atrophy

    2. TET expressiion [30 days]

      - TET expression in tissues with urogenital atrophy

    3. Changes in the 5-hmC [30 days]

      - changes in the 5-hmC content and the 5-mC content in vaginal cells after hormone therapy (topical application of estrogens)

    4. TET expression change [30 days]

      - TET expression change after hormone therapy

    Secondary Outcome Measures

    1. Promoter methylation of specific genes involved in the aging process [30 days]

      - Methylome analysis to identify promoter methylation of specific genes involved in the aging process

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    Female
    Accepts Healthy Volunteers:
    Yes
    Inclusion Criteria:
    • informed consent of the patient

    • patient's age> 18 years

    • POP-Q < = II

    • non-smoker

    • without prior vaginal surgery

    Exclusion Criteria:
    • refusal to participate in the study

    • POP-Q > II

    • smoking

    • internal diseases (diabetes, disorders of the thyroid gland, obesity, cancer, malnutrition, exhaustion)

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Centrum Medyczne "ŻELAZNA" Warsaw Poland 01-004

    Sponsors and Collaborators

    • Żelazna Medical Centre, LLC
    • Laboratory of Genetics and Human Genomics, University of Gdańsk

    Investigators

    None specified.

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Jacek Szymański, Jacek Szymański MD, PhD, Żelazna Medical Centre, LLC
    ClinicalTrials.gov Identifier:
    NCT05318989
    Other Study ID Numbers:
    • 1
    First Posted:
    Apr 8, 2022
    Last Update Posted:
    Apr 8, 2022
    Last Verified:
    Apr 1, 2022
    Keywords provided by Jacek Szymański, Jacek Szymański MD, PhD, Żelazna Medical Centre, LLC

    Study Results

    No Results Posted as of Apr 8, 2022