Endocrine and metabolomic profile and the effectiveness of melatonin as a preconception intervention in women with recurrent assisted reproductive technology failure
Biryukova D.A., Berdnikova A.I., Patskova P.O., Aksenenko A.A., Lapina V.S., Novoselova A.V., Chagovets V.V., Frankevich V.E., Gavisova A.A.
Objective. To characterize the endocrine and metabolomic profile of women with recurrent assisted reproductive technology failure and to evaluate the effectiveness of oral melatonin administration as a preconception intervention for improving ART outcomes in this patient population
Materials and methods. This study enrolled 100 women aged 25–40 years who presented at the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology, and Perinatology for infertility treatment. Oocyte retrieval was performed during IVF cycles conducted either under controlled ovarian stimulation or in a natural cycle. Participants were stratified into four groups: group 1 comprised 37 women with recurrent assisted reproductive technology failure and diminished ovarian reserve (anti-Mullerian hormone [AMH] <1.2 ng/mL; antral follicle count [AFC] <5); group 2 included 18 women with recurrent assisted reproductive technology failure but preserved ovarian reserve (AMH≥1.2 ng/mL; AFC≥5); group 3 (melatonin group) consisted of 18 women with recurrent assisted reproductive technology failure and diminished ovarian reserve (AMH<1.2 ng/mL; AFC<5) who received oral melatonin 3 mg daily for one month before initiation of the ART cycle; and group 4 (control group) included 27 oocyte donors with preserved ovarian reserve (AMH ≥1.2 ng/mL; AFC ≥5). Peripheral blood samples were collected from all participants on days 2–3 of the menstrual cycle before ART initiation, and follicular fluid was collected on the day of transvaginal oocyte retrieval. Amino acid profiles, melatonin and 6-hydroxymelatonin (6-OH-melatonin) concentrations were quantified using liquid chromatography–mass spectrometry (LS–MS). The effectiveness of melatonin treatment was evaluated by comparing the total number of retrieved oocytes, number of mature metaphase II (MII) oocytes, number of normally fertilized zygotes (2PN), fertilization rate, number of blastocysts obtained and cryopreserved, and clinical pregnancy rates between groups 1 and 3.
Results. Compared with the control group, women in group 1 demonstrated lower relative concentrations of phenylalanine, tryptophan, melatonin, and 6-OH-melatonin, and higher concentrations of glycine, glutamine, and glutamic acid (glutamate) in peripheral blood. Follicular fluid obtained from group 1 was characterized by lower relative levels of phenylalanine, glutamine, glutamic acid, tryptophan, melatonin, and 6-OH-melatonin, as well as elevated glycine concentrations, a pattern that was not observed in oocyte donors (group 4). Comparative analysis of endocrine and metabolomic profile of serum and clinical parameters revealed moderate negative correlations between glutamine, glutamic acid, and phenylalanine concentrations and both the total number of oocytes retrieved during ART and clinical pregnancy rates. Moderate positive correlations were identified between serum melatonin levels and the total number of retrieved oocytes, and between serum 6-OH-melatonin concentrations and clinical pregnancy rates. Correlation analysis of endocrine and metabolomic profile of the follicular fluid demonstrated moderate negative associations between glycine concentrations and indicators of oogenesis and early embryogenesis, whereas phenylalanine levels showed moderate positive correlations with the total number of mature oocytes and the number of blastocysts obtained and cryopreserved. Strong positive correlations were observed between follicular fluid tryptophan and melatonin concentrations and the parameters of oogenesis, early embryonic development, and clinical pregnancy.
Conclusion. This study evaluated the effectiveness of melatonin as a preconception intervention in women with recurrent assisted reproductive technology failure. These findings indicate that amino acid and melatonin concentrations are closely associated with key parameters of folliculogenesis and early embryogenesis, suggesting that melatonin supplementation may influence the metabolic pathways involved in amino acid metabolism.
Authors’ contributions. Biryukova D.A., Gavisova A.A. – collection and processing of material, the search and analysis of literature, drafting of the manuscript, editing and final approval of the manuscript, design of the study; Berdnikova A.I., Patskova P.O., Aksenenko A.A., V.S. Lapina – material collection and reviewing; Novoselova A.V. – development of the method for LC–MS analysis of amino acids and hormones in serum and follicular fluid, preparation of blood and follicular fluid samples, conducting analysis, processing of experimental data; V.V. Chagovets, V.E. Frankevich – statistical analysis, reviewing, final approval of the manuscript.
Conflicts of interest. The authors have no conflicts of interest to declare.
Funding. Grant of the Russian Science Foundation No. 24-64-00006, https://rscf.ru/project/24-64-00006/
Ethical Approval. The study was reviewed and approved by the Research Ethics Committee of the V.I. Kulakov NMRC for OG&P.
Generative Artificial Intelligence. No artificial intelligence tools were used in the preparation of this manuscript.
Patient Consent for Publication. All patients provided informed consent for the publication of their data.
Authors' Data Sharing Statement. The data supporting the findings of this study are available upon request from the corresponding author after approval from the principal investigator.
For citation: Biryukova D.A., Berdnikova A.I., Patskova P.O., Aksenenko A.A., Lapina V.S., Novoselova A.V.,
Chagovets V.V., Frankevich V.E., Gavisova A.A. Endocrine and metabolomic profile and the effectiveness of melatonin as a preconception intervention in women with recurrent assisted reproductive technology failure.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2026; (7): 102-113 (in Russian)
https://dx.doi.org/10.18565/aig.2026.74
Keywords
melatonin
amino acids
oxidative stress
diminished ovarian reserve
recurrent assisted reproductive technology failure
follicular fluid
endocrine and metabolomic profile
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Received 22.04.2026
Accepted 26.06.2026
About the Authors
Daria A. Biryukova, gynecologist at the 1st Gynecological Department of the Institute of Reproductive Medicine, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, d_birukova@oparina4.ruAnastasia I. Berdnikova, PhD student at the 1st Gynecological Department of the Institute of Reproductive Medicine, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, berdnikova8002@mail.ru
Polina O. Patskova, PhD student at the 1st Gynecological Department of the Institute of Reproductive Medicine, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, p_lvova@oparina4.ru,
https://orcid.org/0009-0005-6805-2944
Artem A. Aksenenko, PhD, gynecologist at the 1st Gynecological Department of the Institute of Reproductive Medicine, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, a_axenenko@oparina4.ru
Vera S. Lapina, PhD, gynecologist at the 1st Gynecological Department of the Institute of Reproductive Medicine, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, v_lapina@oparina4.ru
Anastasia V. Novoselova, Researcher at the Laboratory of Metabolomics and Bioinformatics, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, aequus@ro.ru
Vitaly V. Chagovets, PhD, Head of the Laboratory of Metabolomics and Bioinformatics, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, vvchagovets@gmail.com, https://orcid.org/0000-0002-5120-376X
Vladimir E. Frankevich, Dr. Sci. (in Physics and Mathematics), Director of the Institute of Translational Medicine, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, v_vfrankevich@oparina4.ru,
https://orcid.org/0000-0002-9780-4579
Alla A. Gavisova, Dr. Med. Sci., Head of the 1st Gynecological Departament, Institute of Reproductive Medicine, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, a_gavisova@oparina4.ru,
https://orcid.org/0000-0003-4700-2786
Corresponding author: Daria A. Biryukova, d_birukova@oparina4.ru
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