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Archives of Gynecology and Obstetrics

, Volume 300, Issue 1, pp 223–233 | Cite as

The effect of luteal GnRH antagonist on moderate and severe early ovarian hyperstimulation syndrome during in vitro fertilization treatment: a prospective cohort study

  • Cheng Zeng
  • Jing Shang
  • Ao-Ming Jin
  • Pei-Li Wu
  • Xin Li
  • Qing XueEmail author
Gynecologic Endocrinology and Reproductive Medicine

Abstract

Purpose

Ovarian hyperstimulation syndrome (OHSS) is a serious complication of assisted reproductive technology (ART) treatment. However, there are limited data regarding the ability of the luteal GnRH antagonist cetrorelix to reduce the incidence of moderate and severe OHSS, and the mechanism remains unclear. Thus, we designed a study to assess the effectiveness of cetrorelix to prevent early moderate and severe OHSS in high-risk patients undergoing controlled ovarian stimulation for IVF/ICSI.

Methods

In this prospective cohort study, 105 patients with high-risk OHSS undergoing cryopreservation of all embryos were divided into two groups according to their personal choice. The cetrorelix group (n = 65) received 0.25 mg of cetrorelix by subcutaneous injection daily, from days 3 to 5 post-oocyte retrieval (POR); the control group (n = 40) received no drug. The primary outcome measures were the incidence and severity of early moderate and severe OHSS. Secondary measures included serum estradiol levels, ovarian volume, ascites volume, hematocrit values, and WBC count on days 3, 6, and 9 POR. VEGF and EGR-1 levels were assessed, and binary logistic regression analysis was applied to predict associations between clinical variables and OHSS.

Results

Ninety-six patients were examined. The incidence of moderate and severe OHSS was significantly lower in the cetrorelix group than in the control group (18.03% and 37.14%, respectively; P = 0.037). Serum estradiol (P = 0.013), white blood cell count (P = 0.031), ascites volume (P = 0.036), EGR-1 (P = 0.025), and VEGF levels (P = 0.015) were significantly higher in the control group on day 6 POR than on day 3 POR, while no increase was observed between day 3 POR and day 6 POR in the cetrorelix group, indicating a faster regression of OHSS symptoms. Cetrorelix intervention was associated with the incidence and severity of OHSS (OR 0.29, 95% CI 0.11–0.78, P = 0.014).

Conclusion

Cetrorelix effectively reduces the incidence of early moderate and severe OHSS in high-risk women and decreases serum VEGF levels.

Keywords

GnRH antagonist Dopamine agonist OHSS VEGF IVF 

Notes

Author contributions

CZ: study design, data management and analysis, and manuscript writing/editing. JS: project development. AMJ: data analysis. PLW and XL: data collection and management. QX: study design, project development, and manuscript editing. All authors read and approved the final manuscript.

Funding

This work was supported by the National Key R&D Program of China (2017YFC1001200).

Compliance with ethical standards

Conflict of Interest

The authors declare that they have no competing interests.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional ethics review board of Peking University First Hospital and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Blumenfeld Z (2018) The ovarian hyperstimulation syndrome. Vitam Horm 107:423–451.  https://doi.org/10.1016/bs.vh.2018.01.018 CrossRefGoogle Scholar
  2. 2.
    Lyons CA, Wheeler CA, Frishman GN, Hackett RJ, Seifer DB, Haning RV Jr (1994) Early and late presentation of the ovarian hyperstimulation syndrome: two distinct entities with different risk factors. Hum Reprod 9(5):792–799CrossRefGoogle Scholar
  3. 3.
    Golan A, Ron-el R, Herman A, Soffer Y, Weinraub Z, Caspi E (1989) Ovarian hyperstimulation syndrome: an update review. Obstet Gynecol Surv 44(6):430–440CrossRefGoogle Scholar
  4. 4.
    Corbett S, Shmorgun D, Claman P, Cheung A, Sierra S, Carranza-Mamane B, Case A, Dwyer C, Graham J, Havelock J, Healey S, Hemmings R, Liu K, Motan T, Murdock W, Smithson D, Vause T, Wong B, Gysler M (2014) The prevention of ovarian hyperstimulation syndrome. J Obstetr Gynaecol Can 36(11):1024–1033.  https://doi.org/10.1016/s1701-2163(15)30417-5 CrossRefGoogle Scholar
  5. 5.
    Nastri CO, Teixeira DM, Moroni RM, Leitao VM, Martins WP (2015) Ovarian hyperstimulation syndrome: pathophysiology, staging, prediction and prevention. Ultrasound Obstet Gynecol 45(4):377–393.  https://doi.org/10.1002/uog.14684 CrossRefGoogle Scholar
  6. 6.
    Busso CE, Garcia-Velasco J, Gomez R, Alvarez C, Simon C, Pellicer A (2009) Symposium: Update on prediction and management of OHSS. Prevention of OHSS--dopamine agonists. Reprod Biomed Online 19(1):43–51Google Scholar
  7. 7.
    Orvieto R, Dratviman-Storobinsky O, Lantsberg D, Haas J, Mashiach R, Cohen Y (2014) Interleukin-2 and SOCS-1 proteins involvement in the pathophysiology of severe ovarian hyperstimulation syndrome–a preliminary proof of concept. J Ovarian Res 7:106.  https://doi.org/10.1186/s13048-014-0106-2 CrossRefGoogle Scholar
  8. 8.
    Guvendag Guven ES, Dilbaz S, Duraker R, Mentese A, Cinar O, Ozdegirmenci O (2013) The effect of cabergoline on folicular microenviroment profile in patients with high risk of OHSS. Gynecol Endocrinol 29(8):749–753.  https://doi.org/10.3109/09513590.2013.801440 CrossRefGoogle Scholar
  9. 9.
    Shimoyamada H, Yazawa T, Sato H, Okudela K, Ishii J, Sakaeda M, Kashiwagi K, Suzuki T, Mitsui H, Woo T, Tajiri M, Ohmori T, Ogura T, Masuda M, Oshiro H, Kitamura H (2010) Early growth response-1 induces and enhances vascular endothelial growth factor-A expression in lung cancer cells. Am J Pathol 177(1):70–83.  https://doi.org/10.2353/ajpath.2010.091164 CrossRefGoogle Scholar
  10. 10.
    Smith V, Osianlis T, Vollenhoven B (2015) Prevention of ovarian hyperstimulation syndrome: a review. Obstet Gynecol Int 2015:514159.  https://doi.org/10.1155/2015/514159 CrossRefGoogle Scholar
  11. 11.
    Tang H, Mourad S, Zhai SD, Hart RJ (2016) Dopamine agonists for preventing ovarian hyperstimulation syndrome. Cochrane Database Syst Rev 11:CD008605.  https://doi.org/10.1002/14651858.CD008605.pub3
  12. 12.
    Sahin N, Apaydin N, Toz E, Sivrikoz ON, Genc M, Turan GA, Cengiz H, Eskicioglu F (2016) Comparison of the effects of letrozole and cabergoline on vascular permeability, ovarian diameter, ovarian tissue VEGF levels, and blood PEDF levels, in a rat model of ovarian hyperstimulation syndrome. Arch Gynecol Obstetr 293(5):1101–1106.  https://doi.org/10.1007/s00404-015-3987-4 CrossRefGoogle Scholar
  13. 13.
    Naredi N, Singh SK, Lele P, Nagraj N (2018) Severe ovarian hyperstimulation syndrome: can we eliminate it through a multipronged approach? Med J Armed Forces India 74(1):44–50.  https://doi.org/10.1016/j.mjafi.2017.04.006 CrossRefGoogle Scholar
  14. 14.
    Lainas GT, Kolibianakis EM, Sfontouris IA, Zorzovilis IZ, Petsas GK, Tarlatzi TB, Tarlatzis BC, Lainas TG (2012) Outpatient management of severe early OHSS by administration of GnRH antagonist in the luteal phase: an observational cohort study. Reprod Biol Endocrinol 10:69.  https://doi.org/10.1186/1477-7827-10-69 CrossRefGoogle Scholar
  15. 15.
    Lainas GT, Kolibianakis EM, Sfontouris IA, Zorzovilis IZ, Petsas GK, Lainas TG, Tarlatzis BC (2013) Pregnancy and neonatal outcomes following luteal GnRH antagonist administration in patients with severe early OHSS. Hum Reprod 28(7):1929–1942.  https://doi.org/10.1093/humrep/det114 CrossRefGoogle Scholar
  16. 16.
    Lainas GT, Kolibianakis EM, Sfontouris IA, Zorzovilis IZ, Petsas GK, Lainas TG, Tarlatzis BC (2014) Serum vascular endothelial growth factor levels following luteal gonadotrophin-releasing hormone antagonist administration in women with severe early ovarian hyperstimulation syndrome. BJOG 121(7):848–855.  https://doi.org/10.1111/1471-0528.12572 CrossRefGoogle Scholar
  17. 17.
    Papanikolaou EG, Humaidan P, Polyzos NP, Tarlatzis B (2010) Identification of the high-risk patient for ovarian hyperstimulation syndrome. Semin Reprod Med 28(6):458–462.  https://doi.org/10.1055/s-0030-1265671 CrossRefGoogle Scholar
  18. 18.
    Navot D, Bergh PA, Laufer N (1992) Ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment. Fertil Steril 58(2):249–261CrossRefGoogle Scholar
  19. 19.
    Prevention and treatment of moderate and severe ovarian hyperstimulation syndrome: a guideline (2016). Fertility and sterility 106(7):1634–1647.  https://doi.org/10.1016/j.fertnstert.2016.08.048
  20. 20.
    Luke B, Brown MB, Morbeck DE, Hudson SB, Coddington CC 3rd, Stern JE (2010) Factors associated with ovarian hyperstimulation syndrome (OHSS) and its effect on assisted reproductive technology (ART) treatment and outcome. Fertil Steril 94(4):1399–1404.  https://doi.org/10.1016/j.fertnstert.2009.05.092 CrossRefGoogle Scholar
  21. 21.
    Jayaprakasan K, Chan Y, Islam R, Haoula Z, Hopkisson J, Coomarasamy A, Raine-Fenning N (2012) Prediction of in vitro fertilization outcome at different antral follicle count thresholds in a prospective cohort of 1,012 women. Fertil Steril 98(3):657–663.  https://doi.org/10.1016/j.fertnstert.2012.05.042 CrossRefGoogle Scholar
  22. 22.
    Steward RG, Lan L, Shah AA, Yeh JS, Price TM, Goldfarb JM, Muasher SJ (2014) Oocyte number as a predictor for ovarian hyperstimulation syndrome and live birth: an analysis of 256,381 in vitro fertilization cycles. Fertil Steril 101(4):967–973.  https://doi.org/10.1016/j.fertnstert.2013.12.026 CrossRefGoogle Scholar
  23. 23.
    Zhou J, Wang B, Hu Y, Sun H (2017) Association between the number of oocytes retrieved and cumulative live birth rate in women aged 35–40 years undergoing long GnRH agonist IVF/ICSI cycles. Arch Gynecol Obstetr 296(5):1005–1012.  https://doi.org/10.1007/s00404-017-4503-9 CrossRefGoogle Scholar
  24. 24.
    Ashrafi M, Bahmanabadi A, Akhond MR, Arabipoor A (2015) Predictive factors of early moderate/severe ovarian hyperstimulation syndrome in non-polycystic ovarian syndrome patients: a statistical model. Arch Gynecol Obstetr 292(5):1145–1152.  https://doi.org/10.1007/s00404-015-3723-0 CrossRefGoogle Scholar
  25. 25.
    Abramov Y, Barak V, Nisman B, Schenker JG (1997) Vascular endothelial growth factor plasma levels correlate to the clinical picture in severe ovarian hyperstimulation syndrome. Fertil Steril 67(2):261–265.  https://doi.org/10.1016/s0015-0282(97)81908-5 CrossRefGoogle Scholar
  26. 26.
    Pau E, Alonso-Muriel I, Gomez R, Novella E, Ruiz A, Garcia-Velasco JA, Simon C, Pellicer A (2006) Plasma levels of soluble vascular endothelial growth factor receptor-1 may determine the onset of early and late ovarian hyperstimulation syndrome. Hum Reprod 21(6):1453–1460.  https://doi.org/10.1093/humrep/del005 CrossRefGoogle Scholar
  27. 27.
    Eftekhar M, Miraj S, Mortazavifar Z (2016) The effect of luteal phase gonadotropin-releasing hormone antagonist administration on IVF outcomes in women at risk of OHSS. Int J Reprod Biomed (Yazd) 14(8):507–510CrossRefGoogle Scholar
  28. 28.
    Asimakopoulos B, Nikolettos N, Nehls B, Diedrich K, Al-Hasani S, Metzen E (2006) Gonadotropin-releasing hormone antagonists do not influence the secretion of steroid hormones but affect the secretion of vascular endothelial growth factor from human granulosa luteinized cell cultures. Fertil Steril 86(3):636–641.  https://doi.org/10.1016/j.fertnstert.2006.01.046 CrossRefGoogle Scholar
  29. 29.
    Wang TH, Horng SG, Chang CL, Wu HM, Tsai YJ, Wang HS, Soong YK (2002) Human chorionic gonadotropin-induced ovarian hyperstimulation syndrome is associated with up-regulation of vascular endothelial growth factor. J Clin Endocrinol Metabol 87(7):3300–3308.  https://doi.org/10.1210/jcem.87.7.8651 CrossRefGoogle Scholar
  30. 30.
    Chen SU, Chou CH, Lin CW, Lee H, Wu JC, Lu HF, Chen CD, Yang YS (2010) Signal mechanisms of vascular endothelial growth factor and interleukin-8 in ovarian hyperstimulation syndrome: dopamine targets their common pathways. Hum Reprod 25(3):757–767.  https://doi.org/10.1093/humrep/dep432 CrossRefGoogle Scholar
  31. 31.
    Guo B, Tian XC, Li DD, Yang ZQ, Cao H, Zhang QL, Liu JX, Yue ZP (2014) Expression, regulation and function of Egr1 during implantation and decidualization in mice. Cell Cycle 13(16):2626–2640.  https://doi.org/10.4161/15384101.2014.943581 CrossRefGoogle Scholar
  32. 32.
    Rong Y, Hu F, Huang R, Mackman N, Horowitz JM, Jensen RL, Durden DL, Van Meir EG, Brat DJ (2006) Early growth response gene-1 regulates hypoxia-induced expression of tissue factor in glioblastoma multiforme through hypoxia-inducible factor-1-independent mechanisms. Cancer Res 66(14):7067–7074.  https://doi.org/10.1158/0008-5472.can-06-0346 CrossRefGoogle Scholar
  33. 33.
    Hosseini MA, Mahdavi A, Aleyasin A, Safdarian L, Bahmaee F (2012) Treatment of ovarian hyperstimulation syndrome using gonadotropin releasing hormone antagonist: a pilot study. Gynecol Endocrinol 28(11):853–855.  https://doi.org/10.3109/09513590.2012.683076 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Obstetrics and GynecologyPeking University First HospitalBeijingPeople’s Republic of China
  2. 2.Peking University Clinical Research Institute, Peking University Health Science CenterBeijingPeople’s Republic of China
  3. 3.Beijing Key Laboratory of Maternal Fetal Medicine of Gestational Diabetes MellitusBeijingPeople’s Republic of China

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