Immune and regenerative mechanisms in the pathogenesis of vulvovaginal atrophy: proteomic analysis of cervicovaginal fluid

DOI

https://dx.doi.org/10.18565/aig.2025.278

Starodubtseva N.L., Nazarova N.M., Devyatkina A.R., Tokareva A.O., Kukaev E.N., Bugrova A.E., Brzhozovskiy A.G., Mezhevitinova E.A., Dovletkhanova E.R., Kepsha E.A., Frankevich V.E., Prilepskaya V.N., Sukhikh G.T.
1) Academician V.I. Kulakov National Medical Research Centre For Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, Moscow, Russia; 2) Moscow Institute of Physics and Technology, Dolgoprudny, Russia; 3) Emanuel Institute of Biochemical Physics of the Russian Academy of Sciences, Moscow Russia; 4) Skolkovo Institute of Science and Technology, Moscow; 5) Siberian State Medical University, Ministry of Health of Russia, Tomsk, Russia

Objective: Exploration of the relationship between clinical and anamnestic data, the severity of VVA, and the results of proteomic analysis of CVF to identify protein biomarkers associated with atrophic changes, inflammation, immune response, and tissue regeneration in the age group of 50–70 years.
Materials and methods: The methodological foundation of this study was a comprehensive analysis integrating the clinical and anamnestic data and proteomic analysis of cervicovaginal fluid (CVF) from patients with vulvovaginal atrophy (VVA). The study included 32 women aged 50–70 years with vulvovaginal atrophy (VVA). The comprehensive analysis included the clinical and anamnestic data, cytological examination, HPV genotyping, and analysis of the protein content of CVF. Semi-quantitative proteomic analysis (HPLC-MS/MS) including protein identification and annotation was performed using the MaxQuant and STRING software packages.
Results: Proteomic analysis of CVF identified specific protein profiles indicating activation of inflammatory processes, impaired tissue regeneration, and neurobiological mechanisms of pain sensitization. These profiles involved protein groups associated with blood microparticles and translocation of SLC2A4, both of which play an important role in occurrence of atrophic changes. Changes in PGAM1, PGAM2, and PGAM4 suggest impaired energy metabolism and the extracellular matrix synthesis, adversely affecting the proliferative activity of epithelial cells. Impaired glycine-serine metabolism reduces collagen and glutathione synthesis contributing to loss of tissue elasticity and increased susceptibility to oxidative stress. Changes in synthesis of HSPA1A and HSPA1B are associated with impaired cellular adaptive responses and lead to accumulation of damaged proteins and enhanced apoptotic death of vaginal epithelial cells.
Conclusion: Proteomic analysis identified specific protein profiles indicating inflammatory activation, impaired tissue regeneration, and neurobiological pathways of pain sensitization.

Authors' contributions: The authors made substantial contributions to drafting the article and approved the final version before publication: Sukhikh G.T. – research concept and design; Nazarova N.M., Mezhevitinova E.A., Dovletkhanova E.R., Kepsha M.A. – data acquisition and processing; Starodubtseva N.L., Tokareva A.O., Kukaev E.N., Bugrova A.E., Brzhozovskiy A.G. – proteomic sample preparation and performance of proteomic analysis; Starodubtseva N.L., Tokareva A.O., Brzhozovskiy A.G., Kukaev E.N. – statistical data processing; Nazarova , N.M., Devyatkina A.R., Starodubtseva N.L., Tokareva A.O., Kukaev E.N., Bugrova A.E., Brzhozovskiy A.G. – manuscript writing; Frankevich V.E., Prilepskaya V.N. – editing and final approval of the manuscript for publication.
Conflicts of interest: The authors confirm that they have no conflicts of interest to declare.
Funding: The study was carried out within the framework of the State Assignment No. № 12503063216-9 on the topic: “Development of a test system for early and minimally invasive diagnosis of HPV-associated precancerous and oncological diseases of the anogenital region in women of different ages using liquid biopsy”
Ethical Approval: The study was approved by the local Ethics Committee of V.I. Kulakov National Medical Research Centre for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia (Protocol No. 1 of January 30, 2025).
Patient Consent for Publication: All patients have signed informed consent for participation in the study and publication of their data.
Authors' Data Sharing Statement: The data supporting the findings of this study are available on request from the corresponding author after approval from the principal investigator.
For citation: Starodubtseva N.L., Nazarova N.M., Devyatkina A.R., Tokareva A.O., Kukaev E.N., Bugrova A.E., Brzhozovskiy A.G., Mezhevitinova E.A., Dovletkhanova E.R., Kepsha E.A., Frankevich V.E., Prilepskaya V.N.,
Sukhikh G.T. Immune and regenerative mechanisms in the pathogenesis of vulvovaginal atrophy:
proteomic analysis of cervicovaginal fluid
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2025; (12): 120-132 (in Russian)
https://dx.doi.org/10.18565/aig.2025.278

cervicovaginal fluid

proteomic analysis

liquid chromatography–mass spectrometry

vulvovaginal atrophy

dyspareunia

GSM

genitourinary syndrome of menopause

Full text (in Russian)

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Received 02.10.2025

Accepted 19.12.2025

Natalia L. Starodubtseva, PhD (Bio), Head of the Laboratory of Clinical Proteomics, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 4, Oparina str., Moscow, 117997, Russia, n_starodubtseva@oparina4.ru, https://orcid.org/0000-0001-6650-5915
Niso M. Nazarova, Dr. Med. Sci., Leading Researcher, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 4, Oparina str., Moscow, 117997, Russia, n_nazarova@oparina4.ru, https://orcid.org/0000-0001-9499-7654
Anastasia R. Devyatkina, obstetrician-gynecologist, PhD student, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 4, Oparina str., Moscow, 117997, Russia, grinasta26@mail.ru, https://orcid.org/0009-0006-1742-7555
Alisa O. Tokareva, PhD (Phys.-Math.), Specialist at the Laboratory of Clinical Proteomics, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 4, Oparina str., Moscow, 117997, Russia, alisa.tokareva@phystech.edu, https://orcid.org/0000-0001-5918-9045
Evgenii N. Kukaev, PhD (Phys.-Math.), PhD, Senior Researcher at the Laboratory of Clinical Proteomics, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 4, Oparina str., Moscow, 117997, Russia; Moscow Institute of Physics and Technology, e_kukaev@oparina4.ru, https://orcid.org/0000-0002-8397-3574
Anna E. Bugrova, PhD (Bio), Senior Researcher at the Laboratory of Proteomics of Human Reproduction, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 4, Oparina str., Moscow, 117997, Russia; Senior Researcher, Laboratory of Neurochemistry, Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, a_bugrova@oparina4.ru
Alexander G. Brzhozovskiy, PhD (Bio), Senior Researcher at the Laboratory of Proteomics of Human Reproduction, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 4, Oparina str., Moscow, 117997; Junior Researcher at the Laboratory of Mass Spectrometry,
Skolkovo Institute of Science and Technology, agb.imbp@gmail.com
Elena A. Mezhevitinova, Dr. Med. Sci., Leading Researcher at the Scientific and Polyclinic Department, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 4, Oparina str., Moscow, 117997, mejevitinova@mail.ru, https://orcid.org/0000-0003-2977-9065
Elmira R. Dovletkhanova, PhD, Senior Researcher at the Scientific and Polyclinic Department, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 4, Oparina str., Moscow, 117997, eldoc@mail.ru, https://orcid.org/0000-0003-2835-6685
Maria A. Kepsha, Junior Researcher, doctor at the Scientific and Polyclinic Department, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 4, Oparina str., Moscow, 117997, m_kepsha@oparina4.ru, https://orcid.org/0000-0002-4201-1360
Vladimir E. Frankevich, Dr. Sci. (Phys.-Math.), Deputy Director of the Institute of Translational Medicine, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 4, Oparina str., Moscow, 117997; Siberian State Medical University, Ministry of Health of Russia,
v_frankevich@oparina4.ru, https://orcid.org/0000-0002-9780-4579
Vera N. Prilepskaya, Dr. Med. Sci., Professor, Honored Scientist of the Russian Federation, Head of the Scientific and Polyclinic Department, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 4, Oparina str., Moscow, 117997, v_prilepskaya@oparina4.ru,
https://orcid.org/0000-0003-3993-7629
Gennady T. Sukhikh, Dr. Med. Sci., Professor, Academician of the RAS, Director, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 4, Oparina str., Moscow, 117997, sekretariat@oparina4.ru, https://orcid.org/0000-0002-7712-1260

Immune and regenerative mechanisms in the pathogenesis of vulvovaginal atrophy: proteomic analysis of cervicovaginal fluid

Starodubtseva N.L., Nazarova N.M., Devyatkina A.R., Tokareva A.O., Kukaev E.N., Bugrova A.E., Brzhozovskiy A.G., Mezhevitinova E.A., Dovletkhanova E.R., Kepsha E.A., Frankevich V.E., Prilepskaya V.N., Sukhikh G.T.

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