Clinical response to controlled ovarian stimulation in IVF programs in women with anovulatory infertility: a pilot study
- Authors: Lapshtaeva A.V.1, Sychev I.V.2, Puzakova D.V.1, Kostina Y.A.1, Adamchik A.I.3, Chilova R.A.4, Sychev D.A.2,5
-
Affiliations:
- N.P. Ogarev National Research Mordovian State University
- B.V. Petrovsky Russian Scientific Center of Surgery
- Mordovian Republican Central Clinical Hospital
- I.M. Sechenov First Moscow State Medical University
- Russian Medical Academy of Continuous Professional Education
- Issue: Vol 33, No 4 (2026)
- Pages: 161-171
- Section: Obstetrics/gynecology
- Published: 17.08.2026
- URL: https://journals.eco-vector.com/2073-4034/article/view/717309
- DOI: https://doi.org/10.18565/pharmateca.2026.4.161-171
- ID: 717309
Cite item
Abstract
Background: Dysfunction of the hypothalamic-pituitary-ovarian axis, leading to anovulation, is one of the most common causes of female reproductive dysfunction. When conservative hormonal therapy is ineffective, in vitro fertilization (IVF) programs with controlled ovarian stimulation (COS) are necessary. To improve the clinical efficacy of IVF programs, the search for additional markers that can predict the pharmacological response to COS is essential.
Objective: Evaluation of the relationship between polymorphic variants of the cytochrome P450 (CYP) genes: CYP1A1, CYP1A2, CYP17A1, and CYP19A1, and the main parameters of clinical response to COS in women with anovulation.
Materials and methods: This prospective cohort study included 60 patients with anovulatory infertility and normal ovarian reserve (mean age 29.4 ± 3.7 years) undergoing IVF with superovulation stimulation using a short protocol and gonadotropin-releasing hormone antagonists. Genotyping of 18 single nucleotide polymorphisms in the CYP1A1, CYP1A2, CYP17A1, and CYP19A1 genes was performed using the Illumina iScan platform.
Results: Carriage of the T/C rs1048943 genotype of the CYP1A1 gene was associated with a significant reduction in the number of oocytes retrieved. Variants rs10046 (A/A genotype), rs700518 (C/C), and rs1062033 (G/G) of the CYP19A1 gene demonstrated a significant association with the risk of developing a «poor» response (OR = 6.96; 6.96; 6.33, respectively; p < 0.05).
Conclusion: The obtained data from the pilot study demonstrate an association between CYP family genes and individual responses to COS in patients with anovulatory infertility, highlighting the importance of continued research and the development of personalized stimulation protocols.
About the authors
Anna V. Lapshtaeva
N.P. Ogarev National Research Mordovian State University
Author for correspondence.
Email: av_lapshtaeva@mail.ru
ORCID iD: 0000-0003-4828-2476
SPIN-code: 9138-6257
Cand. Sci. (Med.), Associate Professor, Associate Professor at the Department of Immunology, Microbiology, and Virology with a Course in Clinical Immunology and Allergology
Russian Federation, SaranskI. V. Sychev
B.V. Petrovsky Russian Scientific Center of Surgery
Email: sychev_iv@bk.ru
ORCID iD: 0000-0002-6454-2349
SPIN-code: 5162-3779
Researcher at the World-Class Genomic Research Center «Center for Predictive Genetics, Pharmacoge Department of Clinical Pharmacology and Personalized Therapy»
Russian Federation, MoscowD. V. Puzakova
N.P. Ogarev National Research Mordovian State University
Email: dashapuzakova.puzakova@yandex.ru
ORCID iD: 0009-0003-3442-1225
SPIN-code: 8812-1945
5th-year student, General Medicine specialty, Medical Institute
Russian Federation, SaranskY. A. Kostina
N.P. Ogarev National Research Mordovian State University
Email: av_lapshtaeva@mail.ru
Russian Federation, Saransk
A. I. Adamchik
Mordovian Republican Central Clinical Hospital
Email: bikbaeva87@inbox.ru
ORCID iD: 0009-0009-1856-2750
Head of the Department of Assisted Reproductive Technologies
Russian Federation, SaranskR. A. Chilova
I.M. Sechenov First Moscow State Medical University
Email: chilova_r_a@staff.sechenov.ru
SPIN-code: 4137-4848
Dr. Sci. (Med.), Associate Professor, Head of the Department of Obstetrics and Gynecology No. 1
Russian Federation, MoscowD. A. Sychev
B.V. Petrovsky Russian Scientific Center of Surgery; Russian Medical Academy of Continuous Professional Education
Email: d.a.sychev.rmapo@rambler.ru
ORCID iD: 0000-0002-4496-3680
SPIN-code: 4525-7556
Dr. Sci. (Med.), Professor, Academician of the Russian Academy of Sciences, Scientific Director of the World-Class Genomic Research Center «Center for Predictive Genetics, Pharmacoge Department of Clinical Pharmacology and Personalized Therapy», Head of the Department of Clinical Pharmacology and Therapy named after academician B.E. Votchal
Russian Federation, Moscow; MoscowReferences
- Анварова Ш.А., Шукуров Ф.И., Туламетова Ш.А. Инновационные методы решения проблемы женского бесплодия, ассоциированного с эндокринными нарушениями. Акушерство, гинекология и репродукция. 2024;18(5):706–19. [Anvarova Sh.A., Shukurov F.I., Tulametova Sh.A. Innovative approaches to solving the problem of female infertility associated with endocrine disorders. Obstet Gynecol Reproduct. 2024;18(5):706–19. (In Russ.)]. https://doi.org/10.17749/2313-7347/ob.gyn.rep.2024.527
- Перминова С.Г., Белова И.С., Митюрина Е.В., Савостина Г.В. Современные подходы к диагностике и ведению пациенток с «бедным» ответом на гонадотропную овариальную стимуляцию в программах вспомогательных репродуктивных технологий. Акушерство и гинекология. 2022;8:12–21. [Perminova S.G., Belova I.S., Mityurina E.V., Savostina G.V. Current approaches to the diagnosis and management of patients with poor response to gonadotropin ovarian stimulation in assisted reproductive technology programs. Obstet Gynecol. 2022;8:12–21. (In Russ.)]. https://dx.doi.org/10.18565/aig.2022.8.12-21
- Башмакова Н.В., Новоселова Е.Н., Назаренко Т.А. и др. Реальная клиническая практика лечения бесплодия в России: коллективное мнение 425 репродуктологов. Акушерство, гинекология и репродукция. 2023;17(6):680–706. [Bashmakova N.V., Novoselova E.N., Nazarenko T.A., et al. Real-world clinical practice of infertility treatment in Russia: a collective opinion of 425 reproductive specialists. Obstet Gynecol Reproduct. 2023;17(6):680–706. (In Russ.)]. https://doi.org/10.17749/2313-7347/ob.gyn.rep.2023.468
- Zhao P., Wang X., Zhang Q., et al. GnRH antagonist protocol versus long-acting GnRH agonist protocol on pregnancy outcomes in IVF/ICSI: a retrospective cohort study. Ann Med. 2025;57(1):2564279. https://doi.org/10.1080/07853890.2025.2564279
- Zhu J., Xing W., Li T., et al. Antagonist Protocol Versus GnRH Agonist Long Protocol: A Retrospective Cohort Study on Clinical Outcomes and Maternal-Neonatal Safety. Front Endocrinol. 2022;13:875779. https://doi.org/10.3389/fendo.2022.875779
- Денисенко М.В., Бондаренко В.Н., Бреслав И.Ю. и др. Ретроспективный анализ исходов программ экстракорпорального оплодотворения у женщин с различным состоянием овариального резерва. Акушерство и гинекология: Новости. Мнения. Обучения. 2025;13(2):7–17. [Denisenko M.V., Bondarenko V.N., Breslav I.Yu., et al. Retrospective analysis of in vitro fertilization outcomes in women with different ovarian reserve status. Obstet Gynecol: News, Opinions, Training. 2025;13(2):7–17. (In Russ.)]. https://doi.org/10.33029/2303-9698-2025-13-2-7-17
- Olivennes F., Trew G., Borini A., et al. Randomized, controlled, open-label, non-inferiority study of the CONSORT algorithm for individualized dosing of follitropin alfa. Reprod Biomed Online. 2015;30(3):248–57. https://doi.org/10.1016/j.rbmo.2014.11.013
- Friis Petersen J., Løkkegaard E., Andersen L.F., et al. A randomized controlled trial of AMH-based individualized FSH dosing in a GnRH antagonist protocol for IVF. Hum Reprod Open. 2019(1):hoz003. https://doi.org/10.1093/hropen/hoz003
- Ngwenya O., Lensen S.F., Vail A., et al. Individualised gonadotropin dose selection using markers of ovarian reserve for women undergoing in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI). Cochrane Database Syst Rev. 2024;1(1):CD012693. https://doi.org/10.1002/14651858.CD012693.pub3
- Pouly J.L., Olivennes F., Massin N., et al.; French CONSORT Study Group. Usability and utility of the CONSORT calculator for FSH starting doses: a prospective observational study. Reprod Biomed Online. 2015;31(3):347–55. https://doi.org/10.1016/j.rbmo.2015.06.001
- You Y., Huang J., Zhu X., Sheng H., Liu Y. Cytochrome P450 (CYP) 1 enzymes in acute lung injury: from molecular insights to therapeutic implications. Redox Rep. 2025;30(1):2550807. https://doi.org/10.1080/13510002.2025.2550807
- Lu J., Shang X., Zhong W., et al. New insights of CYP1A in endogenous metabolism: a focus on single nucleotide polymorphisms and diseases. Acta Pharm Sin B. 2020;10(1):91–104. https://doi.org/10.1016/j.apsb.2019.11.016
- Heidarzadehpilehrood R., Pirhoushiaran M., Abdollahzadeh R., et al. A Review on CYP11A1, CYP17A1, and CYP19A1 Polymorphism Studies: Candidate Susceptibility Genes for Polycystic Ovary Syndrome (PCOS) and Infertility. Genes. 2022;13(2):302. https://doi.org/10.3390/genes13020302
- Mondal S., Shrivastava P., Mehra R. Computing pathogenicity of mutations in human cytochrome P450 superfamily. Biochim Biophys Acta Proteins Proteom. 2025;1873(4):141078. https://doi.org/10.1016/j.bbapap.2025.141078
- Esteves F., Rueff J., Kranendonk M. The central role of cytochrome P450 in xenobiotic metabolism-a brief review on a fascinating enzyme family. J Xenobiot. 2021;11(3):94-114. https://doi.org/10.3390/jox11030007
- Lazaros L.A., Hatzi E.G., Xita N.V., et al. Aromatase (CYP19) gene variants influence ovarian response to standard gonadotrophin stimulation. J Assist Reprod Genet. 2012;29(2):203-9. https://doi.org/10.1007/s10815-011-9673-y
- Song D., Huang X.L., Hong L., et al. Sequence variants in FSHR and CYP19A1 genes and the ovarian response to controlled ovarian stimulation. Fertil Steril. 2019;112(4):749-57. https://doi.org/10.1016/j.fertnstert.2019.05.017
- ILLUMINA. Infinium HTS Assay: Reference Guide. Document # 15045738 v04. November 2019. URL: https://support.illumina.com/content/dam/illumina-support/documents/documentation/chemistry_documentation/infinium_assays/infinium-hts/infinium-hts-assay-reference-guide-15045738-04.pdf (date of access – 19.02.2026).
- Lee A.J., Cai M.X., Thomas P.E., et al. Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms. Endocrinology. 2003;144:3382–98. https://doi.org/10.1210/en.2003-0192
- Sutherland H.G., Champion M., Plays A., et al. Investigation of polymorphisms in genes involved in estrogen metabolism in menstrual migraine. Gene. 2017;607:36–40. https://doi.org/10.1016/j.gene.2017.01.008
- Crofts F., Taioli E., Trachman J., et al. Functional significance of different human CYP1A1 genotypes. Carcinogenesis. 1994;15(12):2961–3. https://doi.org/10.1093/carcin/15.12.2961
- Cosma G., Crofts F., Taioli E., et al. Relationship between genotype and function of the human CYP1A1 gene. J Toxicol Environ Health. 1993;40(2–3):309–16. https://doi.org/10.1080/15287399309531796
- Shen W., Li T., Hu Y., et al. CYP1A1 gene polymorphisms and polycystic ovary syndrome risk: a meta-analysis and meta-regression. Genet Test Mol Biomarkers. 2013;17(10):727–35. https://doi.org/10.1089/gtmb.2013.0209
- Yang H., Xie Y., Yang D., Ren D. Oxidative stress-induced apoptosis in granulosa cells involves JNK, p53 and Puma. Oncotarget. 2017;8(15):25310–22. https://doi.org/10.18632/oncotarget.15813
- Liu S., Jia Y., Meng S., et al. Mechanisms of and Potential Medications for Oxidative Stress in Ovarian Granulosa Cells: A Review. Int J Mol Sci. 2023;24(11):9205. https://doi.org/10.3390/ijms24119205
- Voros C., Chatzinikolaou F., Papadimas G., et al. Oxidative Stress and SIRT1-Nrf2 Anti-Ferroptotic Pathways in Granulosa Cells: A Molecular Key to Follicular Atresia and Ovarian Aging. Int J Mol Sci. 2026;27(2):950. https://doi.org/10.3390/ijms27020950
- Башмакова Н.В., Джалилова Э.Р., Пестряева Л.А., Газиева И.А. Особенности метаболического профиля сыворотки крови и фолликулярной жидкости при «бедном» ответе яичников в программах экстракорпорального оплодотворения. Проблемы репродукции. 2023;29(6):49–56. [Bashmakova N.V., Dzhalilova E.R., Pestryaeva L.A., Gazieva I.A. Features of the metabolic profile of blood serum and follicular fluid in poor ovarian response in in vitro fertilization programs. Rus J Human Reprod. 2023;29(6):49–56. (In Russ.)]. https://doi.org/10.17116/repro20232906149
- Yang X., Yang Y., Xue M., et al. Independent self-construal mediates the association between CYP19A1 gene variant and subjective well-being. Conscious Cogn. 2017;55:205–13. https://doi.org/10.1016/j.concog.2017.08.012
Supplementary files
