Intrafollicular melatonin concentration is elevated in patients with ovarian hyperstimulation syndrome (OHSS) and can serve as an important predictor of OHSS

  • Min Zheng
  • Gaoge Zuo
  • Jing Tong
  • Zi-Jiang Chen
  • Wei-Ping Li
  • Cong ZhangEmail author
Gynecologic Endocrinology and Reproductive Medicine



Melatonin is an important factor in regulating numerous processes in human female reproduction. The aim of the present study was to compare melatonin levels in the follicular fluid (FF) of ovarian hyperstimulation syndrome (OHSS) women with those of non-OHSS women undergoing in vitro fertilization (IVF)-embryo transfer and to evaluate the relationship between FF melatonin levels and IVF outcomes in these women.


We determined FF melatonin levels in 20 OHSS women and 23 non-OHSS women on oocyte retrieval day.


OHSS patients had significantly higher melatonin levels as compared to the non-OHSS women (P < 0.001). In addition, melatonin levels of the patients were significantly positively correlated with antral follicle count (AFC), serum anti-Müllerian hormone (AMH) levels, serum estradiol (E2) levels on human chorionic gonadotropin (HCG) administration day, number of retrieved oocytes, total fertilized oocytes, normally fertilized oocytes, cleaved zygotes, top quality embryos on day 3, blastocysts obtained and embryos suitable for transplantation (day 3 embryos + day 5/6 blastocysts) (P < 0.05). While, the intrafollicular melatonin levels were significantly negatively correlated with age, basal serum follicle-stimulating hormone (FSH) levels, serum FSH levels on HCG administration day (P < 0.01). Since younger women with more AFC, higher AMH levels, higher serum E2 levels and larger number of retrieved oocytes are much easier to encounter OHSS, while FF melatonin levels are significantly correlated with these five indices in our study, we propose that intrafollicular melatonin concentration can also be an important predictor of OHSS.


This is the first demonstration that FF melatonin levels were significantly higher in OHSS patients than in non-OHSS group and FF melatonin levels may serve as an important predictor of OHSS.


Melatonin OHSS AMH IVF Follicular fluid 


Author contributions

CZ: project development and editing, MZ: tissue collection, data analysis, manuscript writing and project development, GZ: tissue collection, JT: tissue collection, W-PL: project development, Z-JC: project development.


This work was supported by a grant from the Major Program of the National Natural Science Foundation of China (81490743) to Z.-J.C.; by grants from National Key R&D Program of China (2017YFC1001403) and the National Natural Science Foundation of China (NSFC: 31671199 and 31871512) to C.Z.; and by the Shanghai Commission of Science and Technology (17DZ2271100).

Compliance with ethical standards

Conflict of interest

All of the authors declare that they have no competing interests.

Ethical approval

All procedures performed in this study involving were in accordance with the ethical standards of the institutional research committee (no. 2015030308) 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.


  1. 1.
    Li HW, Lee VC, Lau EY et al (2014) Cumulative live-birth rate in women with polycystic ovary syndrome or isolated polycystic ovaries undergoing in-vitro fertilization treatment. J Assist Reprod Genet 31(2):205–211PubMedCrossRefGoogle Scholar
  2. 2.
    Nastri CO, Ferriani RA, Rocha IA et al (2010) Ovarian hyperstimulation syndrome: pathophysiology and prevention. J Assist Reprod Genet 27(2):121–128PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Mocanu E, Redmond ML, Hennelly B et al (2007) Odds of ovarian hyperstimulation syndrome (OHSS)-time for reassessment. Hum Fertil (Camb) 10(3):175–181CrossRefGoogle Scholar
  4. 4.
    The Practice Committee of the American Society for Reproductive Medicine (HSRM) (2008) Ovarian hyperstimulation syndrome. Fertil Steril 90(Suppl. 5):S188–S193Google Scholar
  5. 5.
    Practice Committee, of American, Society for, Reproductive M (2008) Ovarian hyperstimulation syndrome. Fertil Steril 90(8):S188–S193Google Scholar
  6. 6.
    Geva E, Jaffe RB (2000) Role of vascular endothelial growth factor in ovarian physiology and pathology. Fertil Steril 74(3):429–438PubMedCrossRefGoogle Scholar
  7. 7.
    Levin ER, Rosen GF, Cassidenti DL et al (1998) Role of vascular endothelial cell growth factor in ovarian hyperstimulation syndrome. J Clin Investig 102(11):1978–1985PubMedCrossRefGoogle Scholar
  8. 8.
    Cui LL, Yang G, Pan J et al (2011) Tumor necrosis factor α knockout increases fertility of mice. Theriogenology 75(5):867–876PubMedCrossRefGoogle Scholar
  9. 9.
    Guo T, Zhang L, Cheng D et al (2015) Low-density lipoprotein receptor affects the fertility of female mice. Reprod Fertil Dev 27(8):1222–1232PubMedCrossRefGoogle Scholar
  10. 10.
    Guo SJ, Yan XY, Shi FF et al (2018) Expression and distribution of the zinc finger protein, SNAI3, in mouse ovaries and pre-implantation embryos. J Reprod Dev 64(2):179–186PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Liu M, Xie S, Zhou J (2018) Use of animal models for the imaging and quantification of angiogenesis. Exp Anim 67(1):1–6PubMedCrossRefGoogle Scholar
  12. 12.
    Papanikolaou EG, Pozzobon C, Kolibianakis EM et al (2006) Incidence and prediction of ovarian hyperstimulation syndrome in women undergoing gonadotropin-releasing hormone antagonist in vitro fertilization cycles. Fertil Steril 85(1):112–120PubMedCrossRefGoogle Scholar
  13. 13.
    Reiter RJ, Tan DX, Manchester LC et al (2009) Melatonin and reproduction revisited. Biol Reprod 81(3):445–456PubMedCrossRefGoogle Scholar
  14. 14.
    Tamura H, Takasaki A, Taketani T et al (2012) The role of melatonin as an antioxidant in the follicle. J Ovarian Res 5(5):5PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Malpaux B, Migaud M, Tricoire H et al (2001) Biology of mammalian photoperiodism and the critical role of the pineal gland and melatonin. J Biol Rhythms 16(4):336–347PubMedCrossRefGoogle Scholar
  16. 16.
    Kauffman AS, Clifton DK, Steiner RA (2007) Emerging ideas about kisspeptin-GPR54 signaling in the neuroendocrine regulation of reproduction. Trends Neurosci 30(10):504–511PubMedCrossRefGoogle Scholar
  17. 17.
    Brzezinski A, Seibel MM, Lynch HJ et al (1987) Melatonin in human preovulatory follicular fluid. J Clin Endocrinol Metab 64(4):865–867PubMedCrossRefGoogle Scholar
  18. 18.
    Rönnberg L, Kauppila A, Leppäluoto J et al (1990) Circadian and seasonal variation in human preovulatory follicular fluid melatonin concentration. J Clin Endocrinol Metab 71(2):492–496PubMedCrossRefGoogle Scholar
  19. 19.
    Nakamura Y, Tamura H, Takayama H et al (2003) Increased endogenous level of melatonin inpreovulatory human follicles does not directly influence progesterone production. Fertil Steril 80(4):1012–1016PubMedCrossRefGoogle Scholar
  20. 20.
    Reiter RJ, Tan DX, Fuentes-Broto L (2010) Melatonin: a multitasking molecule. Prog Brain Res 181(10):127–151PubMedCrossRefGoogle Scholar
  21. 21.
    Tamura H, Nakamura Y, Korkmaz A (2009) Melatonin and the ovary: physiological and pathological implications. Fertil Steril 92(1):328–343PubMedCrossRefGoogle Scholar
  22. 22.
    Whelan JG III, Vlahos NF (2000) The ovarian hyperstimulation syndrome. Fertil Steril 73(5):883–896PubMedCrossRefGoogle Scholar
  23. 23.
    Golan A, Ron-el R, Herman A (1989) Ovarian hyperstimulation syndrome: an update review. Obstet Gynecol Surv 44(6):430–440PubMedCrossRefGoogle Scholar
  24. 24.
    Brinsden PR (1999) A testbook of in vitro fertilization and assisted reproduction. The Parthenon Publishing Group Inc, New YorkGoogle Scholar
  25. 25.
    Gardner PK, Lane M, Stevens J et al (2000) Blastocyst score affects implantation and pregnancy outcome: towards a single blastocyst transfer. Fertil Steril 73(6):1155–1158PubMedCrossRefGoogle Scholar
  26. 26.
    Humaidan P, Quartarolo J, Papanikolaou EG (2010) Preventing ovarian hyperstimulation syndrome: guidance for the clinician. Fertil Steril 94(2):389–400PubMedCrossRefGoogle Scholar
  27. 27.
    Tamura H, Taksaki A, Taketani T et al (2013) Melatonin as a free radical scavenger in the ovarian follicle. Endocr J 60(1):1–13PubMedCrossRefGoogle Scholar
  28. 28.
    Nakamura Y, Smith M, Krishna A (1987) Increased number of mast cells in the dominant follicle of the cow: relationships among luteal, strenal and hilar regions. Biol Reprod 37(3):546–549PubMedCrossRefGoogle Scholar
  29. 29.
    Brannstrom M, Mayrhofer G, Robertson SA (1993) Localization of leucocyte subsets in the rat ovary during the periovulatory period. Biol Reprod 48(2):277–286PubMedCrossRefGoogle Scholar
  30. 30.
    Xie W, Zhou J (2018) Aberrant regulation of autophagy in mammalian diseases. Biol Lett 14(1):1–7CrossRefGoogle Scholar
  31. 31.
    Gupta RK, Mille KP, Babus JK et al (2006) Methoxychlor inhibits growth and induces atresia of antral follicles through an oxidative stress pathway. Toxicol Sci 93(2):382–389PubMedCrossRefGoogle Scholar
  32. 32.
    Korzekwa AJ, Okuda K, Woclawek-Potocka I et al (2006) Nitric oxide induces apoptosis in bovine luteal cells. J Reprod Dev 52(3):353–361PubMedCrossRefGoogle Scholar
  33. 33.
    Lanoix D, Lacasse AA, Reiter RJ et al (2012) Melatonin: the smart killer: the human trophoblast as a model. Mol Cell Endocrinol 348(1):22–28CrossRefGoogle Scholar
  34. 34.
    Zavodnik IB, Domanski AV, Lapshina EA (2006) Melatonin directly scavenges free radicals generated in red blood cells and a cell-free system: chemiluminescence measurements and theoretical calculations. Life Sci 79(4):391–400PubMedCrossRefGoogle Scholar
  35. 35.
    Weenen C, Laven JS, Von Bergh AR et al (2004) Anti-Müllerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment. Mol Hum Reprod 10(2):77–83PubMedCrossRefGoogle Scholar
  36. 36.
    Waldhauser F, Weiszenbacher G, Tatzer E et al (1988) Alterations in nocturnal serum melatonin levels in humans with growth and aging. J Clin Endocrinol Metab 66(3):648–652PubMedCrossRefGoogle Scholar
  37. 37.
    Vakkuri O, Kivelä A, Leppäluoto J et al (1996) Decrease in melatonin precedes follicle-stimulating hormone increase during perimenopause. Eur J Endocrinol 135(2):188–192PubMedCrossRefGoogle Scholar
  38. 38.
    Pappolla MA, Chyan YJ, Poeggeler B et al (2000) An assessment of the antioxidant and the antiamyloidogenic properties of melatonin: implications for Alzheimer’s disease. J Neural Transm 107(2):203–231PubMedCrossRefGoogle Scholar
  39. 39.
    Bonilla E, Valero N, Chacin-Bonilla L (2004) Melatonin and viral infections. J Pineal Res 36(2):73–79PubMedCrossRefGoogle Scholar
  40. 40.
    Hussain SA, Khadim HM, Khalaf BH et al (2006) Effects of melatonin and zinc on glycemic control in type 2 diabetic patients poorly controlled with metformin. Saudi Med J 27(10):1483–1488PubMedGoogle Scholar
  41. 41.
    Lissoni P (2007) Biochemotherapy with standard chemotherapies plus the pineal hormone melatonin in the treatment of advanced solid neoplasms. Pathol Biol 55(3–4):201–204PubMedCrossRefGoogle Scholar
  42. 42.
    Tamura H, Takasaki A, Miwa I et al (2008) Oxidative stress impairs oocyte quality and melatonin protects oocytes from free radical damage and improves fertilization rate. J Pineal Res 44(3):280–287PubMedCrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  1. 1.Center for Reproductive Medicine, School of Medicine, RenJi HospitalShanghai Jiao Tong UniversityShanghaiChina
  2. 2.Key Laboratory of Animal Resistance Research, College of Life ScienceShandong Normal UniversityJinanChina
  3. 3.Shanghai Key Laboratory for Assisted Reproduction and Reproductive GeneticsShanghaiChina
  4. 4.Shanghai Jinshan High SchoolShanghaiChina

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