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      Zonulin as a potential biomarker for diminished ovarian reserve: A prospective study

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          Abstract

          Objective:

          The purpose of this research is to investigate the relationship between zonulin levels and diminished ovarian reserve (DOR), and to evaluate the potential role of autoimmunity in the development of DOR. The study contributes to the understanding of the pathogenesis of DOR, which can be an unexpected diagnosis often associated with infertility and unpleasant physical symptoms in women.

          Materials and Methods:

          This cross-sectional study was conducted by scanning 224 patients. The demographic characteristics of the patients were recorded. Antral follicle counts of the patients were determined by ultrasound, and Anti-Mullerian hormone (AMH) levels were examined. Follicle-stimulating hormone (FSH), luteinizing hormone, estradiol, AMH measurement, and antral follicle counts were made on the 2nd or 3rd day of menstrual bleeding. The zonulin levels of the participants were measured by the ELISA method. The patients were divided into two groups according to the presence of DOR. The patients’ demographic characteristics and hormone levels were compared between these two groups, serum zonulin levels were examined, and the relationship between other hormone parameters and zonulin was investigated.

          Results:

          When the median ages of the patients in both groups were compared, the median age of patients with DOR was 38 years, significantly higher (p<0.001) than the median age of those without DOR, which was 27 years. The median zonulin levels of both groups were compare; it was observed that it was 19.71 ng/mL in the group with DOR and 11.03 ng/mL without DOR, and a statistically significant difference was found between the zonulin levels of the patients in both groups (p<0.001). A moderate inverse correlation (p<0.001) between patients’ zonulin and AMH levels, and a moderate correlation between FSH levels (p<0.001).

          Conclusion:

          In conclusion, zonulin levels of patients with DOR were higher than women without DOR. Evaluation of zonulin levels may also be considered during the diagnosis of DOR.

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          Most cited references21

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          Ovarian aging: mechanisms and clinical consequences.

          F. Broekmans, M Soules, B. C. Fauser (2009)
          Menopause is the final step in the process referred to as ovarian ageing. The age related decrease in follicle numbers dictates the onset of cycle irregularity and the final cessation of menses. The parallel decay in oocyte quality contributes to the gradual decline in fertility and the final occurrence of natural sterility. Endocrine changes mainly relate to the decline in the negative feedback from ovarian factors at the hypothalamo-pituitary unit. The declining cohort of antral follicles with age first results in gradually elevated FSH levels, followed by subsequent stages of overt cycle irregularity. The gradual decline in the size of the antral follicle cohort is best represented by decreasing levels of anti-Mullerian hormone. The variability of ovarian ageing among women is evident from the large variation in age at menopause. The identification of women who have severely decreased ovarian reserve for their age is clinically relevant. Ovarian reserve tests have appeared to be fairly accurate in predicting response to ovarian stimulation in the assisted reproductive technology (ART) setting. The capacity to predict the chances for spontaneous pregnancy or pregnancy after ART appears very limited. As menopause and the preceding decline in oocyte quality seem to have a fixed time interval, tests that predict the age at menopause may be useful to assess individual reproductive lifespan. Especially genetic studies, both addressing candidate gene and genome wide association, have identified several interesting loci of small genetic variation that may determine fetal follicle pool development and subsequent wastage of his pool over time. Improved knowledge of the ovarian ageing mechanisms may ultimately provide tools for prediction of menopause and manipulation of the early steps of folliculogenesis for the purpose of contraception and fertility lifespan extension.
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            Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis

            Narges Tajik, Michael Frech, Oscar Schulz … (2020)
            Gut microbial dysbiosis is associated with the development of autoimmune disease, but the mechanisms by which microbial dysbiosis affects the transition from asymptomatic autoimmunity to inflammatory disease are incompletely characterized. Here, we identify intestinal barrier integrity as an important checkpoint in translating autoimmunity to inflammation. Zonulin family peptide (zonulin), a potent regulator for intestinal tight junctions, is highly expressed in autoimmune mice and humans and can be used to predict transition from autoimmunity to inflammatory arthritis. Increased serum zonulin levels are accompanied by a leaky intestinal barrier, dysbiosis and inflammation. Restoration of the intestinal barrier in the pre-phase of arthritis using butyrate or a cannabinoid type 1 receptor agonist inhibits the development of arthritis. Moreover, treatment with the zonulin antagonist larazotide acetate, which specifically increases intestinal barrier integrity, effectively reduces arthritis onset. These data identify a preventive approach for the onset of autoimmune disease by specifically targeting impaired intestinal barrier function.
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              A new model of reproductive aging: the decline in ovarian non-growing follicle number from birth to menopause.

              Jay Charleston, M Soules, S Knowlton … (2008)
              The primary determinant of reproductive age in women is the number of ovarian non-growing (primordial, intermediate and primary) follicles (NGFs). To better characterize the decline in NGF number associated with aging, we have employed modern stereology techniques to determine NGF number in women from birth to menopause. Normal human ovaries were collected from 122 women (aged 0-51 years) undergoing elective oophorectomy, organ donation or autopsy. After gross pathologic examination, systematic random sampling was utilized to obtain tissue for analysis by the fractionator/optical disector method. Models to describe the resulting decay curve were constructed and evaluated. NGF decay was best described by a simple power function: log (y) = ax(b) + c, where a, b and c are constants and y = NGF count at age x (R(2) = 0.84, Sums of Squares Error = 28.18 on 119 degrees of freedom). This model implies that follicles decay faster with increasing age. Unlike previous models of ovarian follicle depletion, our model predicts no sudden change in decay rate, but rather a constantly increasing rate. The model not only agrees well with observed ages of menopause in women, but also is more biologically plausible than previous models. Although the model represents a significant improvement compared with earlier attempts, a considerable percentage of the variation in NGF number between women cannot be explained by age alone.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Turk J Obstet Gynecol
                Journal ID (iso-abbrev): Turk J Obstet Gynecol
                Journal ID (publisher-id): TJOG
                Title: Turkish Journal of Obstetrics and Gynecology
                Publisher: Galenos Publishing
                ISSN (Print): 2149-9322
                ISSN (Electronic): 2149-9330
                Publication date (Print): June 2023
                Publication date (Electronic): 1 June 2023
                Volume: 20
                Issue: 2
                Pages: 120-125
                Affiliations
                [1 ]Balıkesir State Hospital, Clinic of Obstetrics and Gynecology, Balıkesir, Turkey
                [2 ]Sivas Cumhuriyet University Faculty of Medicine, Department of Obstetrics and Gynecology, Sivas, Turkey
                [3 ]University of Health Sciences Turkey, Samsun Training and Research Hospital, Clinic of Obstetrics and Gynecology, Samsun, Turkey
                Author notes
                * Address for Correspondence: Sivas Cumhuriyet University Faculty of Medicine, Department of Obstetrics and Gynecology, Sivas, Turkey Phone: +90 532 600 85 31 E-mail: nazanyurtcu@ 123456cumhuriyet.edu.tr
                Author information
                https://orcid.org/0000-0002-2631-1603
                https://orcid.org/0000-0003-4725-043X
                https://orcid.org/0000-0002-9889-5249
                https://orcid.org/0000-0002-6407-1129
                Article
                Publisher ID: 60458
                DOI: 10.4274/tjod.galenos.2023.26037
                PMC ID: 10236232
                PubMed ID: 37260186
                SO-VID: e2164dfc-42de-424e-a4c2-3d3c98c1ebcc
                Copyright © ©Copyright 2023 by Turkish Society of Obstetrics and Gynecology | Turkish Journal of Obstetrics and Gynecology published by Galenos Publishing House.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 15 April 2023
                Date accepted : 25 April 2023
                Categories
                Subject: Clinical Investigation

                Keywords: diminished ovarian reserve,zonulin levels,autoimmunity,anti-mullerian hormone,amh,infertility
                Data availability:
                Keywords: diminished ovarian reserve, zonulin levels, autoimmunity, anti-mullerian hormone, amh, infertility

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