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Genetic Aspects of Vaginal Aging

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ClinicalTrials.gov Identifier: NCT05318989
Recruitment Status : Recruiting
First Posted : April 8, 2022
Last Update Posted : April 8, 2022
Sponsor:
Collaborator:
Laboratory of Genetics and Human Genomics, University of Gdańsk
Information provided by (Responsible Party):
Jacek Szymański, Żelazna Medical Centre, LLC

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
Genitourinary Agents

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Study Type : Observational
Estimated 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 : February 8, 2021
Estimated Primary Completion Date : December 28, 2022
Estimated Study Completion Date : December 30, 2022

Resource links provided by the National Library of Medicine


Group/Cohort
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



Primary Outcome Measures :
  1. 5-hmC content [ Time Frame: 30 days ]
    - 5-hmC content and 5-mC increase in tissues with urogenital atrophy

  2. TET expressiion [ Time Frame: 30 days ]
    - TET expression in tissues with urogenital atrophy

  3. Changes in the 5-hmC [ Time Frame: 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 [ Time Frame: 30 days ]
    - TET expression change after hormone therapy


Secondary Outcome Measures :
  1. Promoter methylation of specific genes involved in the aging process [ Time Frame: 30 days ]
    - Methylome analysis to identify promoter methylation of specific genes involved in the aging process


Biospecimen Retention:   Samples With DNA
vaginal swabs, buccal swabs, vaginal wall samples


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population
Study population description: Women treated in Urogynecological Unit of St. Sophia Hospital in Warsaw (outpatients and hospitalized) who meet the inclusion criteria.
Criteria

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05318989


Locations
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Poland
Centrum Medyczne "ŻELAZNA" Recruiting
Warsaw, Poland, 01-004
Contact: Jacek Szymański, MD, PhD    +48222559918    jkszymanski2@gmail.com   
Principal Investigator: Jacek Szymański, MD, PhD         
Sponsors and Collaborators
Żelazna Medical Centre, LLC
Laboratory of Genetics and Human Genomics, University of Gdańsk
Publications:
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Responsible Party: Jacek Szymański, Jacek Szymański MD, PhD, Żelazna Medical Centre, LLC
ClinicalTrials.gov Identifier: NCT05318989    
Other Study ID Numbers: 1
First Posted: April 8, 2022    Key Record Dates
Last Update Posted: April 8, 2022
Last Verified: April 2022
Keywords provided by Jacek Szymański, Żelazna Medical Centre, LLC:
vulvovaginal atrophy
genitourinary syndrome of menopause
aging
5-hydroxymethylcytosine
5-hmC
5-methylcytosine
ten-eleven translocation
TET enzymes