The effect of myo-inositol on the follicular fluid metabolomic profile in women with predicted poor ovarian response undergoing in vitro fertilization: association with oocyte quality
Zakovryashin E.A., Korneeva I.E., Chagovets V.V., Mityurina E.V., Novoselova A.V., Sannikova E.S., Nazarenko T.A., Levin V.A.
Objective: To evaluate the outcomes of IVF and the follicular fluid metabolomic profile in patients with predicted poor ovarian response who received myo-inositol (MI) 1200 mg, alpha-lactalbumin (α-LA), and folic acid 400 mcg at the preconception stage.
Materials and methods: The study included 80 women with a predicted poor ovarian response, belonging to groups 3 and 4 of the POSEIDON classification, who were planning to undergo IVF as part of their infertility treatment. Patients in group 1 received MI 1200 mg, α-LA, and folic acid 400 mcg (Inofert Forte) daily for three months before ovarian stimulation. The women in group 2 received 400 mcg of folic acid. Amino acid and ceramide levels in the follicular fluid were analyzed.
Results: Group 1 showed a significant increase in the number of mature oocytes, zygotes, total blastocysts, and good-quality blastocysts compared with group 2. The use of MI + α-LA resulted in a statistically insignificant increase in the clinical pregnancy rate (27.0% in group 1 versus 10.8% in group 2, p<0.075, OR=3.05 [95% CI: 0.86–10.84]) and ongoing pregnancy rate (21.6% versus 8.1%, respectively, p<0.102, OR=3.13 [95% CI: 0.76–12.88]). The metabolomic profile of women in group 1 was characterized by increased levels of isoleucine, valine, leucine, alpha-aminobutyric acid, histidine, threonine, and proline, along with decreased levels of ceramides Cer (d18:0/24:1), Cer (d18:0/16:0), Cer (d18:0/22:0), Cer (d18:1/23:0), Cer (d18:1/25:0), Cer (d18:2/23:0), and Cer (d18:0/24:0).
Conclusion: Adjuvant therapy with MI before gonadotropic stimulation in patients with a poor ovarian response influences lipid and ceramide metabolism in the follicular microenvironment. This therapy also results in a greater number of mature oocytes and high-quality blastocysts, which positively affects the clinical outcomes of IVF infertility treatment.
Authors’ contributions: Korneeva I.E., Nazarenko T.A. – conception and design of the study; Zakovryashin E.A., Chagovets V.V., Mityurina E.V., Novoselova A.V. – material collection and processing; Zakovryashin E.A., Chagovets V.V., Novoselova A.V., Levin V.A. – statistical analysis; Zakovryashin E.A., Levin V.A. – drafting of the manuscript; Korneeva I.E., Chagovets V.V., Mityurina E.V., Sannikova E.S., Nazarenko T.A. – editing of the manuscript.
Conflicts of interest: The authors have no conflicts of interest to declare.
Funding: There was no funding for this study.
Ethical approval: The study was reviewed and approved by the Research Ethics Committee of the V.I. Kulakov NMRC for OG&P.
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: Zakovryashin E.A., Korneeva I.E., Chagovets V.V., Mityurina E.V., Novoselova A.V., Sannikova E.S., Nazarenko T.A., Levin V.A. The effect of myo-inositol on the follicular fluid metabolomic profile in women with
predicted poor ovarian response undergoing in vitro fertilization: association with oocyte quality.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2025; (4): 94-103 (in Russian)
https://dx.doi.org/10.18565/aig.2025.108
Keywords
in vitro fertilization
infertility
myo-inositol (MI)
alpha-lactalbumin (α-LA)
poor ovarian response
follicular fluid
metabolome
References
- Roberts L.M., Herlihy N., Reig A., Titus S., Garcia-Milian R., Knight J. et al. Transcriptomic landscape of cumulus cells from patients <38 years old with a history of poor ovarian response (POR) treated with platelet-rich plasma (PRP). Aging (Albany NY). 2025; 17(2): 431-47. https://dx.doi.org/10.18632/aging.206202.
- Caprio F., D'Eufemia M.D., Trotta C., Campitiello M.R., Ianniello R., Mele D. et al. Myo-inositol therapy for poor-responders during IVF: a prospective controlled observational trial. J. Ovarian Res. 2015; 8: 37. https://dx.doi.org/10.1186/s13048-015-0167-x.
- Mohammadi S., Eini F., Bazarganipour F., Taghavi S.A., Kutenaee M.A. The effect of Myo-inositol on fertility rates in poor ovarian responder in women undergoing assisted reproductive technique: a randomized clinical trial. Reprod. Biol. Endocrinol. 2021; 19(1): 61. https://dx.doi.org/10.1186/s12958-021-00741-0.
- Nazari L., Salehpour S., Hosseini S., Saharkhiz N., Azizi E., Hashemi T. et al. Effect of myo-inositol supplementation on ICSI outcomes among poor ovarian responder patients: A randomized controlled trial. J. Gynecol. Obstet. Hum. Reprod. 2020; 49(5): 101698. https://dx.doi.org/10.1016/j.jogoh.2020.101698.
- Kamenov Z., Gateva A., Dinicola S., Unfer V. Comparing the efficacy of Myo-inositol plus α-Lactalbumin vs. Myo-inositol alone on reproductive and metabolic disturbances of polycystic ovary syndrome. Metabolites. 2023; 13(6): 717. https://dx.doi.org/10.3390/ metabo13060717.
- Zhang Y., He C., He Y., Zhu Z. Follicular fluid metabolomics: tool for predicting IVF outcomes of different infertility causes. Reprod. Sci. 2025; 32(4): 921-34. https://dx.doi.org/10.1007/s43032-024-01664-y.
- Ибрагимова Л.К., Смольникова В.Ю., Эльдаров Ч.М., Бобров М.Ю., Агаджанян Д.С., Романов Е.А., Калинина Е.А. Особенности метаболомного профиля фолликулярной жидкости и сред культивирования эмбрионов пациенток с наружным генитальным эндометриозом. Акушерство и гинекология. 2021; 11: 114-24. [ Ibragimova L.K., Smol'nikova V.Yu., El'darov Ch.M., Bobrov M.Yu., Agadzhanyan D.S., Romanov E.A., Kalinina E.A. Metabolomic profile of follicular fluid and embryo culture media in patients with extragenital endometriosis. Obstetrics and Gynecology. 2021; (11): 114-24 (in Russian)]. https://dx.doi.org/10.18565/aig.2021.11.114-124.
- Gardner D.K., Schoolcraft W.B. Culture and transfer of human blastocysts. Curr. Opin. Obstet. Gynecol. 1999; 11(3): 307-11. https://dx.doi.org/10.1097/00001703-199906000-00013.
- Placidi M., Casoli G., Tatone C., Di Emidio G., Bevilacqua A. Myo-inositol and its derivatives: their roles in the challenges of infertility. Biology (Basel). 2024; 13(11): 936. https://dx.doi.org/10.3390/biology13110936.
- Вартанян Э.В., Цатурова К.А., Девятов Е.А., Михайлюкова А.С., Левин В.А., Сагамонова К.Ю., Громенко Д.С., Овсянникова Т.В., Эрлихман Н.М., Колосова Е.А., Сафронова Е.В., Фотина О.В., Красновская Е.В., Пожарищенская Т.Г., Аутлева С.Р., Гзгзян А.М., Нуриев И.Р., Воропаева Е.Е., Пестова Т.И., Здановский В.М., Ким Н.А., Котельников А.Н., Сафронов О.В., Назаренко Т.А., Ионова Р.М. Подготовка к лечению бесплодия методом экстракорпорального оплодотворения при сниженном овариальном резерве. Акушерство и гинекология. 2019; 8: 134-42. [Vartanyan E.V., Tsaturova K.A., Devyatova E.A., Mikhailyukova A.S., Levin V.A., Sagamonova K.Yu., Gromenko D.S., Ovsyannikova T.V., Erlikhman N.M., Kolosova E.A., Safronova E.V., Fotina O.V., Krasnovskaya E.V., Pozharischenskaya T.G., Autleva S.R., Gzgzyan A.M., Nuriev I.R., Voropaeva E.E., Pestova T.I., Zdanovsky V.M., Kim N.A., Kotelnikov A.N., Safronov O.V., Nazarenko T.A., Ionova R.M. Preparation for the in vitro fertilization treatment of infertility in diminished ovarian reserve. Obstetrics and Gynecology. 2019; (8): 134-42 (in Russian)]. https://dx.doi.org/10.18565/aig.2019.8.134-142.
- Hemmings K.E., Maruthini D., Vyjayanthi S., Hogg J.E., Balen A.H., Campbell B.K. et al. Amino acid turnover by human oocytes is influenced by gamete developmental competence, patient characteristics and gonadotrophin treatment. Hum. Reprod. 2013; 28(4): 1031-44. https://dx.doi.org/10.1093/humrep/des458.
- Bahrami M., Morris M.B., Day M.L. Glutamine, proline, and isoleucine support maturation and fertilisation of bovine oocytes. Theriogenology. 2023; 201: 59-67. https://dx.doi.org/10.1016/j.theriogenology.2023.02.019.
- Hood R.B., Liang D., Tan Y., Ford J.B., Souter I., Chavarro J.E. et al. Serum and follicular fluid metabolome and markers of ovarian stimulation. Hum. Reprod. 2023; 38(11): 2196-207. https://dx.doi.org/10.1093/humrep/dead189.
- Lazzarino G., Pallisco R., Bilotta G., Listorti I., Mangione R., Saab M.W. et al. Altered follicular fluid metabolic pattern correlates with female infertility and outcome measures of in vitro fertilization. Int. J. Mol. Sci. 2021; 22(16): 8735. https://dx.doi.org/10.3390/ijms22168735.
- Treleaven T., Hardy M.L.M., Guttman-Jones M., Morris M.B., Day M.L. In vitro fertilisation of mouse oocytes in L-Proline and L-Pipecolic acid improves subsequent development. Cells. 2021; 10(6): 1352. https://dx.doi.org/10.3390/cells10061352.
- Van Winkle L.J. Amino acid transport and metabolism regulate early embryo development: species differences, clinical significance, and evolutionary implications. Cells. 2021; 10(11): 3154. https://dx.doi.org/10.3390/cells10113154.
- Correia B., Sousa M.I., Branco A.F., Rodrigues A.S., Ramalho-Santos J. Leucine and arginine availability modulate mouse embryonic stem cell proliferation and metabolism. Int. J. Mol. Sci. 2022; 23(22): 14286. https://dx.doi.org/10.3390/ijms232214286.
- Elgebaly M.M., Hazaa A.B.M., Amer H.A., Mesalam A. L-Cysteine improves bovine oocyte developmental competence in vitro via activation of oocyte-derived growth factors BMP-15 and GDF-9. Reprod. Domest. Anim. 2022; 57(7): 734-42. https://dx.doi.org/10.1111/rda.14113.
- Lee Y., Shim J., Ko N., Kim H.J., Park J.K., Kwak K., Kim H., Choi K. Effect of alanine supplementation during in vitro maturation on oocyte maturation and embryonic development after parthenogenesis and somatic cell nuclear transfer in pigs. Theriogenology. 2019; 127: 80-7. https://dx.doi.org/10.1016/j.theriogenology.2019.01.001
- Гапоненко А.А., Митюрина Е.В., Франкевич В.Е. Метаболомный профиль фолликулярной жидкости как маркер качества ооцитов в программах вспомогательных репродуктивных технологий. Акушерство и гинекология. 2021; 11: 26-31. [Gaponenko A.A., Mityurina E.V., Frankevich V.E. The follicular fluid metabolomic profile as a marker for oocyte quality in assisted reproductive technology programs. Obstetrics and Gynecology. 2021; (11): 26-31 (in Russian)]. https://dx.doi.org/10.18565/aig.2021.11.26-31.
- Wallace M., Cottell E., Gibney M.J., McAuliffe F.M., Wingfield M., Brennan L. An investigation into the relationship between the metabolic profile of follicular fluid, oocyte developmental potential, and implantation outcome. Fertil. Steril. 2012; 97(5): 1078-84.e1-8. https://dx.doi.org/10.1016/j.fertnstert.2012.01.122.
- Luti S., Fiaschi T., Magherini F., Modesti P.A., Piomboni P., Governini L. et al. Relationship between the metabolic and lipid profile in follicular fluid of women undergoing in vitro fertilization. Mol. Reprod. Dev. 2020; 87(9): 986-97. https://dx.doi.org/10.1002/mrd.23415.
- Alizadeh J., da Silva Rosa S.C., Weng X., Jacobs J., Lorzadeh S., Ravandi A. et al. Ceramides and ceramide synthases in cancer: Focus on apoptosis and autophagy. Eur. J. Cell Biol. 2023; 102(3): 151337. https://dx.doi.org/10.1016/j.ejcb.2023.151337.
- Lee S., Kang H.G., Jeong P.S., Kim M.J., Park S.H., Song B.S. et al. Heat stress impairs oocyte maturation through ceramide-mediated apoptosis in pigs. Sci. Total Environ. 2021; 755(Pt 1): 144144. https://dx.doi.org/10.1016/j.scitotenv.2020.144144.
Received 21.04.2025
Accepted 25.04.2025
About the Authors
Evgeniy A. Zakovryashin, PhD student, Academician V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology, Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, +7(916)051-75-36, 324155hf@mail.ru, https://orcid.org/0009-0002-3908-7230Irina Е. Korneeva, Dr. Med. Sci., Professor, Leading Researcher at the Scientific and Educational Center of Auxiliary Reproductive Technologies with a Clinical Department named after Frederick Paulsen, Academician V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology, Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, https://orcid.org/0000-0002-0904-585X
Vitaliy V. Chagovets, PhD, Head of the Laboratory for 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, https://orcid.org/0000-0002-5120-376X
Elena V. Mityurina, PhD, Senior Researcher at the Scientific and Educational Center of Auxiliary Reproductive Technologies with a Clinical Department
named after Frederick Paulsen, 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, https://orcid.org/0000-0001-8830-2158
Anastasia V. Novoselova, Researcher at the Laboratory of Metabolomics and Bioinformatics, Academician V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology, Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4.
Elena S. Sannikova, Embryologist at the Scientific and Educational Center of Auxiliary Reproductive Technologies with a Clinical Department named after Frederick Paulsen, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology, Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, https://orcid.org/0009-0009-2351-3400
Tatiana A. Nazarenko, Dr. Med. Sci., Professor, Head of the Institute of Reproductive Medicine, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology, Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, https://orcid.org/0000-0002-5823-1667
Vitaly A. Levin, Endocrinologist, Ornament Health AG, Lucerne, Switzerland, https://orcid.org/0009-0000-8758-0842
Corresponding author: Evgeniy A. Zakovryashin, 324155hf@mail.ru
Similar Articles
