Angiogenesis factors and hormonal changes in the first half of pregnancy in patients after controlled ovulation stimulation

Authors

DOI:

https://doi.org/10.18370/2309-4117.2026.82.20-25

Keywords:

in vitro fertilization, controlled ovulation stimulation, pregnancy, estradiol, β-human chorionic gonadotropin, vascular endothelial growth factor A, placental growth factor, antioxidant effect

Abstract

Objective of the study: to evaluate the dynamics of early pregnancy hormones and angiogenesis markers in pregnant women after controlled ovarian stimulation (COS).

Materials and methods. 156 patients were divided into 4 groups: Group I – 41 pregnant women who became pregnant after in vitro fertilization (IVF) in a natural cycle, Group II – 43 pregnant women after 1–2 cycles of COS, Group III – 42 pregnant women after 3 or more cycles of COS. 22 patients of subgroup IIA and 21 patients of subgroup IIIA did not receive additional treatment by COS, 21 pregnant women of subgroup IIB and 21 patients of subgroup IIIB were prescribed melatonin to achieve an antioxidant effect. 30 healthy pregnant women with spontaneous pregnancy formed the control group. In all pregnant women at 11–13 weeks, the serum levels of progesterone, estradiol, β-human chorionic gonadotropin (β-hCG), vascular endothelial growth factor A (VEGF-A), placental growth factor (PLGF), soluble fms-like tyrosine kinase receptor (sFlt-1) were determined.

Results. Patients in all groups had no differences in progesterone concentrations, which can be explained by the administration of progesterone as part of implantation support. The estradiol content at the end of the first trimester of pregnancy was lower in patients receiving COS cycles than in women with spontaneous pregnancy, and the β-hCG levels were significantly higher. Such hormonal changes are associated with a higher risk of pregnancy loss. VEGF-A at the transition between the first and second trimesters of pregnancy demonstrates an increase in pregnant women with 3 or more COS cycles, which indicates excessive antiangiogenic activity. PLGF, on the contrary, showed a reduced content in this subgroup of women, which may be the cause of incomplete trophoblast invasion and associated gestational complications. Patients who simultaneously with COS took an antioxidant drug, in terms of the concentration of early pregnancy hormones and angiogenic factors, did not differ from women with spontaneous pregnancy.

Conclusions. Patients who underwent COS within the IVF had signs of functional chorion insufficiency, namely reduced concentration of estradiol and increased content of β-hCG. Pregnant women with 3 or more cycles of COS at the end of the first trimester of pregnancy had a higher level of VEGF-A than women with spontaneous pregnancy, as well as a lower concentration of PLGF. The appointment of antioxidant therapy within the IVF leads to an increase in estradiol, a decrease in β-hCG. Antioxidant therapy in pregnant women with 3 or more cycles of IVF allows to reduce the level of VEGF-A and increase the PLGF content.

Author Biographies

L. Gasanova, Shupyk National Healthcare University of Ukraine, Kyiv

postgraduate student, Department of Obstetrics, Gynecology and Reproductive Medicine

M.N. Shalko, Shupyk National Healthcare University of Ukraine; Kyiv City Center for Reproductive and Perinatal Medicine, Kyiv

PhD, associate professor, Department of Reproductive and Perinatal Medicine
DSc in public administration, deputy director for organizational and methodological work

Y.B. Motsiuk, Ivano-Frankivsk National Medical University, Ivano-Frankivsk

PhD, associate professor, Department of Obstetrics and Gynecology

M.I. Antonyuk, O.O. Bogomolets National Medical University, Kyiv

PhD, assistant, Department of Obstetrics and Gynecology No. 1

References

  1. Carson SA, Kallen AN. Diagnosis and Management of Infertility: A Review. JAMA. 2021 Jul 6;326(1):65-76. DOI: 10.1001/jama.2021.4788.
  2. Infertility Workup for the Women’s Health Specialist: ACOG Committee Opinion Summary, Number 781. Obstet Gynecol. 2019 Jun;133(6):1294–5. DOI: 10.1097/AOG.0000000000003272
  3. Malina A, Błaszkiewicz A, Owczarz U. Psychosocial aspects of infertility and its treatment . Ginekol Pol. 2016, 87:527–31. DOI: 10.5603/GP.2016.0038
  4. Boutari C, Pappas PD, Mintziori G, Nigdelis MP, Athanasiadis L, Goulis DG, et al. The effect of underweight on female and male reproduction. Metabolism. 2020 Jun;107:154229. DOI: 10.1016/j.metabol.2020.154229.
  5. Jiang M, Wang C, Fei X, Lin Z. Pregnancy confirmed after controlled ovarian stimulation for infertility: A case report. Medicine (Baltimore). 2021 Sep 17;100(37):e27140. DOI: 10.1097/MD.0000000000027140.
  6. Bosch E, Broer S, Griesinger G, Grynberg M, Humaidan P, Kolibianakis E, et al. ESHRE guideline: ovarian stimulation for IVF/ICSI†. Hum Reprod Open. 2020 May 1;2020(2):hoaa009. DOI: 10.1093/hropen/hoaa009.
  7. Kanter J, Gordon SM, Mani S, Sokalska A, Park JY, Senapati S, et al. Hormonal stimulation reduces numbers and impairs function of human uterine natural killer cells during implantation. Hum Reprod. 2023 Jun 1;38(6):1047–59. DOI: 10.1093/humrep/dead069.
  8. Mu H, Yu H, Yan S, Lu J, Mao J, Sun D, et al. High concentration of estrogen resulted by COH may affect the secretion of pro-angiogenic factors in uNK cells by downregulating the expression of IL-11 in decidual stromal cells. J Assist Reprod Genet. 2024 Nov;41(11):3189–200. DOI: 10.1007/s10815-024-03241-3.
  9. Özalp Akın E, Aycan Z. Evaluation of the Ovarian Reserve in Adolescents with Hashimoto’s Thyroiditis Using Serum Anti-Müllerian Hormone Levels. J Clin Res Pediatr Endocrinol. 2018 Nov 29;10(4):331–5. DOI: 10.4274/jcrpe.0047.
  10. Aghssa MM, Tarafdari AM, Tehraninejad ES, Ezzati M, Bagheri M, Panahi Z, et al. Optimal cutoff value of basal anti-mullerian hormone in iranian infertile women for prediction of ovarian hyper-stimulation syndrome and poor response to stimulation. Reprod Health. 2015 Sep 10;12:85. DOI: 10.1186/s12978-015-0053-4.
  11. Liu L, Sun XY, Yang H, Feng XJ, Lan YZ. Predictive value of anti-Mullerian hormone for pregnancy outcomes following assisted reproductive techniques (ART) in Southwest China. Reprod Health. 2022 Dec 13;19(1):224. DOI: 10.1186/s12978-022-01524-5.
  12. Conrad KP. Evidence for Corpus Luteal and Endometrial Origins of Adverse Pregnancy Outcomes in Women Conceiving with or Without Assisted Reproduction. Obstet Gynecol Clin North Am. 2020 Mar;47(1):163–81. DOI: 10.1016/j.ogc.2019.10.011.
  13. Cacciottola L, Donnez J, Dolmans MM. Can Endometriosis-Related Oxidative Stress Pave the Way for New Treatment Targets? Int J Mol Sci. 2021 Jul 1;22(13):7138. DOI: 10.3390/ijms22137138.
  14. Zhang X, Gao J, Yang L, Feng X, Yuan X. Oxidative stress and its role in recurrent pregnancy loss: mechanisms and implications. J Mol Histol. 2024 Dec 26;56(1):55. DOI: 10.1007/s10735-024-10332-z.
  15. Ma Y, Zhao Z, Hao G, Cui N, Fan Y, Cao Y, et al. Effects of multicycle gonadotropin-releasing hormone antagonist protocols on oxidative stress of follicular fluid and ovarian granulosa cells. Hum Cell. 2021 Sep;34(5):1324–34. DOI: 10.1007/s13577-021-00545-9.
  16. Reiter RJ, Tan DX, Manchester LC, Lopez-Burillo S, Sainz RM, Mayo JC. Melatonin: detoxification of oxygen and nitrogen-based toxic reactants. Adv Exp Med Biol. 2003;527:539–48. DOI: 10.1007/978-1-4615-0135-0_62.
  17. Espino J, Macedo M, Lozano G, Ortiz Á, Rodríguez C, Rodríguez AB, et al. Impact of Melatonin Supplementation in Women with Unexplained Infertility Undergoing Fertility Treatment. Antioxidants (Basel). 2019 Aug 23;8(9):338. DOI: 10.3390/antiox8090338.
  18. Order of the Ministry of Health of Ukraine No. 787, 9.09.2013 “On approval of the Procedure for the use of assistive reproductive technologies in Ukraine”[Internet]. Ministry of Health of Ukraine ? 2013. Available from: https://zakon.rada.gov.ua/laws/show/z1697-13#Text
  19. Mørch NF, Udengaard H, Borch ML, Saltoft Skovrup M, Nøhr B, Svendsen PF. Estradiol and progesterone levels in early pregnancy after modified natural, programmed, and gonadotrophin-stimulated frozen embryo transfer cycles: a randomized controlled trial. Hum Reprod. 2025 Jul 1;40(7):1291–04. DOI: 10.1093/humrep/deaf083.
  20. Pepe G, Locati M, Della Torre S, Mornata F, Cignarella A, Maggi A, et al. The estrogen-macrophage interplay in the homeostasis of the female reproductive tract. Hum Reprod Update. 2018 Nov 1;24(6):652–72. DOI: 10.1093/humupd/dmy026.
  21. Costa AJ, Oliveira RB, Wachilewski P, Nishino MS, Bassani TB, Stilhano RS, et al. Membrane estrogen receptor ERα activation improves tau clearance via autophagy induction in a tauopathy cell model. Brain Res. 2022 Nov 15;1795:148079. DOI: 10.1016/j.brainres.2022.148079.
  22. Li Q, Ruan L, Zhu L, Yang Z, Zhu M, Luo Y. Elevated estradiol levels in frozen embryo transfer have different effects on pregnancy outcomes depending on the stage of transferred embryos. Sci Rep. 2022 Apr 4;12(1):5592. DOI: 10.1038/s41598-022-09545-7.
  23. Boyle P, Andralojc K, van der Velden S, Najmabadi S, de Groot T, Turczynski C, et al. Restoration of serum estradiol and reduced incidence of miscarriage in patients with low serum estradiol during pregnancy: a retrospective cohort study using a multifactorial protocol including DHEA. Front Reprod Health. 2024 Jan 4;5:1321284. DOI: 10.3389/frph.2023.1321284.
  24. Shoarishoar SS, Milani F, Adineh S, Sorouri ZR, Maryam Attari S. Comparison of pregnancy outcomes in amniocentesis recipients with normal and abnormal maternal serum analytes. Cell Mol Biol (Noisy-le-grand). 2024 Nov 27;70(11):109–14. DOI: 10.14715/cmb/2024.70.11.16.
  25. Chen Y, Dai X, Wu B, Jiang C, Yin Y. Relationship between increased maternal serum free human chorionic gonadotropin levels in the second trimester and adverse pregnancy outcomes: a retrospective cohort study. BMC Womens Health. 2024 Jun 4;24(1):323. DOI: 10.1186/s12905-024-03105-z.
  26. Lee P, Yan N, Fan G, Hu X, Mai Q, Zhou C, et al. Predicting ART outcomes: The role of ovarian RAS and VEGF in follicular fluid of dominant follicles. J Reprod Immunol. 2025 Feb;167:104393. DOI: 10.1016/j.jri.2024.104393.
  27. Benkhalifa M, Zidi W, Bahri H, Mahjoub S, Boudhraa K, Sanhaji H, et al. Circulating MMP-7 and VEGF as potential predictive biomarkers for recurrent implantation failures. Zygote. 2021 Oct;29(5):365–71. DOI: 10.1017/S0967199421000113.
  28. Tokalioglu E, Turgut E, Yildiz EG, Agaoglu M, Biriken D, Tanacan A, et al. Comparison of VEGF-A levels in women with threatened abortion, early pregnancy loss and uncomplicated healthy pregnancies. Cytokine. 2023, V170, 156343. DOI: 10.1016/j.cyto.2023.156343.
  29. Llurba E, Crispi F, Verlohren S. Update on the pathophysiological implications and clinical role of angiogenic factors in pregnancy. Fetal Diagn Ther. 2015;37(2):81–92. DOI: 10.1159/000368605.
  30. Creswell L, O’Gorman N, Palmer KR, da Silva Costa F, Rolnik DL. Perspectives on the Use of Placental Growth Factor (PlGF) in the Prediction and Diagnosis of Pre-Eclampsia: Recent Insights and Future Steps. Int J Womens Health. 2023 Feb 13;15:255–71. DOI: 10.2147/IJWH.S368454.
  31. Barton JR, Woelkers DA, Newman RB, Combs CA, How HY, Boggess KA, et al.; PETRA (Preeclampsia Triage by Rapid Assay) Trial. Placental growth factor predicts time to delivery in women with signs or symptoms of early preterm preeclampsia: a prospective multicenter study. Am J Obstet Gynecol. 2020 Mar;222(3):259.e1–259.e11. DOI: 10.1016/j.ajog.2019.09.003.
  32. Herraiz I, Quezada MS, Rodriguez-Calvo J, Gómez-Montes E, Villalaín C, Galindo A. Longitudinal change of sFlt-1/PlGF ratio in singleton pregnancy with early-onset fetal growth restriction. Ultrasound Obstet Gynecol. 2018 Nov;52(5):631–8. DOI: 10.1002/uog.18894.

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Published

2026-04-18

How to Cite

Gasanova, L., Shalko, M., Motsiuk, Y., & Antonyuk, M. (2026). Angiogenesis factors and hormonal changes in the first half of pregnancy in patients after controlled ovulation stimulation. REPRODUCTIVE ENDOCRINOLOGY, (82), 20–25. https://doi.org/10.18370/2309-4117.2026.82.20-25

Issue

No. 82 (2026)

Section

Pregnancy and childbirth

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