Skip to main content
SpringerLink
Log in

Associations between IVF outcomes and essential trace elements measured in follicular fluid and urine: a pilot study

  • Reproductive Physiology and Disease
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

A hypothesis-generating pilot study exploring associations between essential trace elements measured in follicular fluid (FF) and urine and in vitro fertilization (IVF) endpoints.

Methods

We recruited 58 women undergoing IVF between 2007 and 2008, and measured cobalt, chromium, copper, manganese, molybdenum, and zinc in FF (n = 46) and urine (n = 45) by inductively coupled plasma mass spectrometry (ICP-MS). We used multivariable regression models to assess the impact of FF and urine trace elements on IVF outcomes, adjusted for age, body mass index, race, and cigarette smoking.

Results

Trace elements were mostly present at lower concentrations in FF than in urine. The average number of oocytes retrieved was positively associated with higher urine cobalt, chromium, copper, and molybdenum concentrations. FF chromium and manganese were negatively associated with the proportion of mature oocytes, yet urine manganese had a positive association. FF zinc was inversely associated with average oocyte fertilization. Urine trace elements were significant positive predictors for the total number of embryos generated. FF copper predicted lower embryo fragmentation while urine copper was associated with higher embryo cell number and urine manganese with higher embryo fragmentation. No associations were detected for implantation, pregnancy, or live birth.

Conclusions

Our results suggest the importance of trace elements in both FF and urine for intermediate, although not necessarily clinical, IVF endpoints. The results differed using FF or urine biomarkers of exposure, which may have implications for the design of clinical and epidemiologic investigations. These initial findings will form the basis of a more definitive future study.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Chandra A, Copen CE, National Center for Health Statistics, Stephen EH. Infertility service use in the United States: data from the National Survey of Family Growth, 1982–2010. Hyattsville, MD: U.S. Centers for Disease Control and Prevention; 2014.

  2. Sunderam S, Kissin DM, Crawford SB, Folger SG, Jamieson DJ, Warner L, et al. Assisted reproductive technology surveillance—United States, 2013. MMWR Surveill Summ. 2015;64:1–25.

    Article  Google Scholar 

  3. Katz P, Showstack J, Smith JF, Nachtigall RD, Millstein SG, Wing H, et al. Costs of infertility treatment: results from an 18-month prospective cohort study. Fertil Steril. 2011;95:915–21.

    Article  PubMed  Google Scholar 

  4. Cassidy T, Sintrovani P. Motives for parenthood, psychosocial factors and health in women undergoing IVF. J Reprod Infant Psychol. 2008;26:4–17.

    Article  Google Scholar 

  5. Zhao J, Li YP, Zhang Q, Wang YG. Does ovarian stimulation for IVF increase gynaecological cancer risk? A systematic review and meta-analysis. Reprod Biomed Online. 2015;31:20–9.

    Article  PubMed  Google Scholar 

  6. Ata B, Tulandi T. Pathophysiology of ovarian hyperstimulation syndrome and strategies for its prevention and treatment. Expert Rev Obstet Gynecol. 2009;4:299–311.

    Article  Google Scholar 

  7. Schieve LA, Cohen B, Nannini A, Ferre C, Reynolds MA, Zhang Z, et al. A population-based study of maternal and perinatal outcomes associated with assisted reproductive technology in Massachusetts. Matern Child Health J. 2007;11:517–25.

    Article  PubMed  Google Scholar 

  8. Bogden JD, Klevay LM. Clinical nutrition of the essential trace elements and minerals: the guide for health professionals. Totowa: Humana Press; 2000.

    Book  Google Scholar 

  9. Fraga CG. Relevance, essentiality and toxicity of trace elements in human health. Mol Asp Med. 2005;26:235–44.

    Article  CAS  Google Scholar 

  10. Schwarz G, Mendel RR, Ribbe MW. Molybdenum cofactors, enzymes and pathways. Nature. 2009;460:839–47.

    Article  CAS  PubMed  Google Scholar 

  11. Vincent JB. Elucidating a biological role for chromium at a molecular level. Acc Chem Res. 2000;33:503–10.

    Article  CAS  PubMed  Google Scholar 

  12. Banerjee R, Ragsdale SW. The many faces of vitamin B-12: catalysis by cobalamin-dependent enzymes. Annu Rev Biochem. 2003;72:209–47.

    Article  CAS  PubMed  Google Scholar 

  13. Keen CL, Ensunsa JL, Watson MH, Baly DL, Donovan SM, Monaco MH, et al. Nutritional aspects of manganese from experimental studies. Neurotoxicology. 1999;20:213–23.

    CAS  PubMed  Google Scholar 

  14. Borowiecka M, Wojsiat J, Polac I, Radwan M, Radwan P, Zbikowska HM. Oxidative stress markers in follicular fluid of women undergoing in vitro fertilization and embryo transfer. Syst Biol Reprod Med. 2012;58:301–5.

    Article  CAS  PubMed  Google Scholar 

  15. Jana SK, K NB, Chattopadhyay R, Chakravarty B, Chaudhury K. Upper control limit of reactive oxygen species in follicular fluid beyond which viable embryo formation is not favorable. Reprod Toxicol. 2010;29:447–451.

  16. Bloom MS, Parsons PJ, Steuerwald AJ, Schisterman EF, Browne RW, Kim K, et al. Toxic trace metals and human oocytes during in vitro fertilization (IVF). Reprod Toxicol. 2010;29:298–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bloom MS, Kim K, Kruger PC, Parsons PJ, Arnason JG, Steuerwald AJ, et al. Associations between toxic metals in follicular fluid and in vitro fertilization (IVF) outcomes. J Assist Reprod Genet. 2012;29:1369–79.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Fujimoto VY, Browne RW, Bloom MS, Sakkas D, Alikani M. Pathogenesis, developmental consequences, and clinical correlations of human embryo fragmentation. Fertil Steril. 2011;95:1197–204.

    Article  PubMed  Google Scholar 

  19. Holte J, Berglund L, Milton K, Garello C, Gennarelli G, Revelli A, et al. Construction of an evidence-based integrated morphology cleavage embryo score for implantation potential of embryos scored and transferred on day 2 after oocyte retrieval. Hum Reprod. 2007;22:548–57.

    Article  CAS  PubMed  Google Scholar 

  20. Zegers-Hochschild F, Adamson GD, de Mouzon J, Ishihara O, Mansour R, Nygren K, et al. The International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) revised glossary on ART terminology, 2009. Hum Reprod. 2009;24:2683–7.

    Article  CAS  PubMed  Google Scholar 

  21. Kruger PC, Bloom MS, Arnason JG, Palmer CD, Fujimoto VY, Parsons PJ. Trace elements in human follicular fluid: development of a sensitive multielement ICP-MS method for use in biomonitoring studies. J Anal At Spectrom. 2012;27:1245–53.

    Article  CAS  Google Scholar 

  22. Schisterman EF, Vexler A, Whitcomb BW, Liu A. The limitations due to exposure detection limits for regression models. Am J Epidemiol. 2006;163:374–83.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Kim K, Steuerwald AJ, Parsons PJ, Fujimoto VY, Browne RW, Bloom MS. Biomonitoring for exposure to multiple trace elements via analysis of urine from participants in the Study of Metals and Assisted Reproductive Technologies (SMART). J Environ Monit. 2011;13:2413–9.

    Article  CAS  PubMed  Google Scholar 

  24. Barr DB, Wilder LC, Caudill SP, Gonzalez AJ, Needham LL, Pirkle JL. Urinary creatinine concentrations in the U.S. population: implications for urinary biologic monitoring measurements. Environ Health Perspect. 2005;113:192–200.

    Article  CAS  PubMed  Google Scholar 

  25. Wellons MF, Fujimoto VY, Baker VL, Barrington DS, Broomfield D, Catherino WH, et al. Race matters: a systematic review of racial/ethnic disparity in society for assisted reproductive technology reported outcomes. Fertil Steril. 2012;98:406–9.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Maheshwari A, Stofberg L, Bhattacharya S. Effect of overweight and obesity on assisted reproductive technology—a systematic review. Hum Reprod Update. 2007;13:433–44.

    Article  CAS  PubMed  Google Scholar 

  27. Hughes EG, Brennan BG. Does cigarette smoking impair natural or assisted fecundity? Fertil Steril. 1996;66:679–89.

    Article  CAS  PubMed  Google Scholar 

  28. Piette C, de Mouzon J, Bachelot A, Spira A. In-vitro fertilization: influence of women’s age on pregnancy rates. Hum Reprod. 1990;5:56–9.

    CAS  PubMed  Google Scholar 

  29. Yelland LN, Salter AB, Ryan P. Performance of the modified Poisson regression approach for estimating relative risks from clustered prospective data. Am J Epidemiol. 2011;174:984–92.

    Article  PubMed  Google Scholar 

  30. Zou G. A modified Poisson regression approach to prospective studies with binary data. Am J Epidemiol. 2004;159:702–6.

    Article  PubMed  Google Scholar 

  31. Kleinbaum DG, Kupper LL, Muller KE, Nizam A. Regression diagnostics. In: Kleinbaum DG, Kupper LL, Muller KE, Nizham A, editors. Applied regression analysis and other multivariable methods. Pacific Grove: Duxbury Press; 1998. p. 212–80.

    Google Scholar 

  32. CLSI: EP28-A3C: defining, establishing, and verifying reference intervals in the clinical laboratory; approved guideline—third edition. Wayne 2008.

  33. Centers for Disease Control and Prevention. National Center for Health Statistics. National Health and Nutrition Examination Survey Data. 2007–2008 [cited 15 Oct 2015]; Available fom: http://wwwn.cdc.gov/nchs/nhanes/search/nhanes07_08.aspx.

  34. Centers for Disease Control and Prevention. National Center for Health Statistics (NCHS). National Health and Nutrition Examination Survey Data. 2011–2012 [cited 15 Oct 2015]; Available fom: http://www.cdc.gov/nchs/nhanes.htm.

  35. Bloom MS, Louis GMB, Sundaram R, Kostyniak PJ, Jain J. Associations between blood metals and fecundity among women residing in New York State. Reprod Toxicol. 2011;31:158–63.

    Article  CAS  PubMed  Google Scholar 

  36. Bernhardt ML, Kong BY, Kim AM, O’Halloran TV, Woodruff TK. A zinc-dependent mechanism regulates meiotic progression in mammalian oocytes. Biol Reprod. 2012;86:114.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Jeon Y, Yoon JD, Cai L, Hwang SU, Kim E, Zheng Z, et al. Supplementation of zinc on oocyte in vitro maturation improves preimplatation embryonic development in pigs. Theriogenology. 2014;82:866–74.

    Article  CAS  PubMed  Google Scholar 

  38. Hanna LA, Peters JM, Wiley LM, Clegg MS, Keen CL. Comparative effects of essential and nonessential metals on preimplantation mouse embryo development in vitro. Toxicology. 1997;116:123–31.

    Article  CAS  PubMed  Google Scholar 

  39. Hanna LA, Clegg MS, Momma TY, Daston GP, Rogers JM, Keen CL. Zinc influences the in vitro development of peri-implantation mouse embryos. Teratology. 2003;67:414–20.

    CAS  Google Scholar 

  40. Ng SC, Karunanithy R, Edirisinghe WR. Human follicular fluid levels of calcium, copper and zinc. Gynecol Obstet Investig. 1987;23:129–32.

    Article  CAS  Google Scholar 

  41. Singh AK, Chattopadhyay R, Chakravarty B, Chaudhury K. Markers of oxidative stress in follicular fluid of women with endometriosis and tubal infertility undergoing IVF. Reprod Toxicol. 2013;42:116–24.

    Article  CAS  PubMed  Google Scholar 

  42. Zhang YL, Liu FJ, Chen XL, Zhang ZQ, Shu RZ, Yu XL, et al. Dual effects of molybdenum on mouse oocyte quality and ovarian oxidative stress. Syst Biol Reprod Med. 2013;59:312–8.

    Article  CAS  PubMed  Google Scholar 

  43. Anchordoquy JP, Anchordoquy JM, Sirini MA, Mattioli G, Picco SJ, Furnus CC. Effect of different manganese concentrations during in vitro maturation of bovine oocytes on DNA integrity of cumulus cells and subsequent embryo development. Reprod Domest Anim. 2013;48:905–11.

    Article  CAS  PubMed  Google Scholar 

  44. Attaran M, Pasqualotto E, Falcone T, Goldberg JM, Miller KF, Agarwal A, et al. The effect of follicular fluid reactive oxygen species on the outcome of in vitro fertilization. Int J Fertil Womens Med. 2000;45:314–20.

    CAS  PubMed  Google Scholar 

  45. Agarwal A, Aponte-Mellado A, Premkumar B, Shaman A, Gupta S. The effects of oxidative stress on female reproduction: a review. Reprod Biol Endocrinol. 2012;10:49.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Hawk SN, Uriu-Hare JY, Daston GP, Jankowski MA, Kwik-Uribe C, Rucker RB, et al. Rat embryos cultured under copper-deficient conditions develop abnormally and are characterized by an impaired oxidant defense system. Teratology. 1998;57:310–20.

    Article  CAS  PubMed  Google Scholar 

  47. Kikuchi I, Takeuchi H, Kinoshita K, Shinohara A, Chiba M, Inaba H. Measurement of the essetial element concentration in follicular fluid. Nihon Funin Gakkai Zasshi. 2002;47:131–7.

    CAS  Google Scholar 

  48. Boxmeer JC, Macklon NS, Lindemans J, Beckers NGM, Eijkemans MJC, Laven JSE, et al. IVF outcomes are associated with biomarkers of the homocysteine pathway in monofollicular fluid. Hum Reprod. 2009;24:1059–66.

    Article  CAS  PubMed  Google Scholar 

  49. Gaskins AJ, Chiu YH, Williams PL, Ford JB, Toth TL, Hauser R, et al. Association between serum folate and vitamin B-12 and outcomes of assisted reproductive technologies. Am J Clin Nutr. 2015;102:943–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Silberstein T, Saphier O, Paz-Tal O, Gonzalez L, Keefe DL, Trimarchi JR. Trace element concentrations in follicular fluid of small follicles differ from those in blood serum, and may represent long-term exposure. Fertil Steril. 2009;91:1771–4.

    Article  CAS  PubMed  Google Scholar 

  51. Wang YX, Feng W, Zeng Q, Sun Y, Wang P, You L, et al. Variability of metal levels in spot, first morning, and 24-hour urine samples over a 3-month period in healthy adult Chinese men. Environ Health Perspect. 2016;124:468–76.

    PubMed  Google Scholar 

  52. Saglam HS, Altundag H, Atik YT, Dundar MS, Adsan O. Trace elements levels in the serum, urine, and semen of patients with infertility. Turk J Med Sci. 2015;45:443–8.

    Article  CAS  PubMed  Google Scholar 

  53. Datta J, Palmer MJ, Tanton C, Gibson LJ, Jones KG, Macdowall W, et al. Prevalence of infertility and help seeking among 15 000 women and men. Hum Reprod. 2016;31:2108–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Rothman KJ, Greenland S, Lash TL. Modern epidemiology. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2008. p. 758.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Epidemiology and Biostatistics, University at Albany, State University of New York, Rensselaer, NY, USA

    Mary E. Ingle & Michael S. Bloom

  2. Department of Environmental Health Sciences, University at Albany, State University of New York, Rensselaer, NY, USA

    Michael S. Bloom & Patrick J. Parsons

  3. School of Public Health, University at Albany, State University of New York, Rm. #149, One University Place, Rensselaer, NY, 12144, USA

    Michael S. Bloom

  4. Laboratory of Inorganic and Nuclear Chemistry, Wadsworth Center, New York State Department of Health, Albany, NY, USA

    Patrick J. Parsons, Amy J. Steuerwald & Pamela Kruger

  5. Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California at San Francisco, San Francisco, CA, USA

    Victor Y. Fujimoto

Authors
  1. Mary E. Ingle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael S. Bloom
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Patrick J. Parsons
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amy J. Steuerwald
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pamela Kruger
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Victor Y. Fujimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael S. Bloom.

Ethics declarations

Conflict of interest

The authors declare they have no conflicts of interest.

Additional information

Capsule Our results suggest the importance of trace elements in both FF and urine for intermediate, although not necessarily clinical, IVF endpoints.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Table S1

(DOC 45.5 kb)

Table S2

(DOC 50 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ingle, M.E., Bloom, M.S., Parsons, P.J. et al. Associations between IVF outcomes and essential trace elements measured in follicular fluid and urine: a pilot study. J Assist Reprod Genet 34, 253–261 (2017). https://doi.org/10.1007/s10815-016-0853-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10815-016-0853-7

Keywords

Search

Navigation