DOI QR코드

DOI QR Code

Sex as an important biological variable in biomedical research

  • Lee, Suk Kyeong (Department of Medical Lifescience, College of Medicine, The Catholic University of Korea)
  • Received : 2018.01.24
  • Published : 2018.04.30

Abstract

Experimental results obtained from research using only one sex are sometimes extrapolated to both sexes without thorough justification. However, this might cause enormous economic loss and unintended fatalities. Between years 1997 and 2000, the US Food and Drug Administration suspended ten prescription drugs producing severe adverse effects on the market. Eight of the ten drugs caused greater health risks in women. Serious male biases in basic, preclinical, and clinical research were the main reason for the problem. This mini-review will describe why and how funding organizations such as the European Commission, the Canadian Institutes of Health Research, and the US National Institutes of Health have tried to influence researchers to integrate sex/gender not only in clinical research, but also in basic and preclinical research. Editorial policies of prominent journals for sex-specific reporting will also be introduced, and some considerations in integrating sex as a biological variable will be pointed out. To produce precise and reproducible results applicable for both men and women, sex should be considered as an important biological variable from basic and preclinical research.

Keywords

Animal;Biological variable;Cell;Female;Funding;Gender;Journal;Male;Preclinical research;Sex

Acknowledgement

Supported by : NRF

References

  1. GAO-01-286R. (available at https://www.gao.gov/new.items/d01286r.pdf).
  2. Hughes RN (2007) Sex does matter: comments on the prevalence of male-only investigations of drug effects on rodent behaviour. Behav Pharmacol 18, 583-589 https://doi.org/10.1097/FBP.0b013e3282eff0e8
  3. GAO, Women's Health-FDA Needs to Ensure More Study of Gender Differences in Prescription Drug Testing (available at http://archive.gao.gov/d35t11/147861.pdf).
  4. Gochfeld M (2017) Sex Differences in Human and Animal Toxicology. Toxicol Pathol 45, 172-189 https://doi.org/10.1177/0192623316677327
  5. Institute of Medicine (2001) in Exploring the Biological Contributions to Human Health: Does Sex Matter?, Wizemann TM and Pardue ML (eds.), Washington (DC)
  6. Regitz-Zagrosek V (2012) Sex and gender differences in pharmacology, Springer, Berlin; New York
  7. Yoon DY, Mansukhani NA, Stubbs VC, Helenowski IB, Woodruff TK and Kibbe MR (2014) Sex bias exists in basic science and translational surgical research. Surgery 156, 508-516 https://doi.org/10.1016/j.surg.2014.07.001
  8. Sechzer JA, Rabinowitz VC, Denmark FL, McGinn MF, Weeks BM and Wilkens CL (1994) Sex and gender bias in animal research and in clinical studies of cancer, cardiovascular disease, and depression. Ann N Y Acad Sci 736, 21-48 https://doi.org/10.1111/j.1749-6632.1994.tb12816.x
  9. Clayton JA and Tannenbaum C (2016) Reporting Sex, Gender, or Both in Clinical Research? JAMA 316, 1863-1864 https://doi.org/10.1001/jama.2016.16405
  10. Miller VM (2012) In pursuit of scientific excellence: sex matters. Am J Physiol Gastrointest Liver Physiol 302, G907-908 https://doi.org/10.1152/ajpgi.00101.2012
  11. Beery AK and Zucker I (2011) Sex bias in neuroscience and biomedical research. Neurosci Biobehav Rev 35, 565-572 https://doi.org/10.1016/j.neubiorev.2010.07.002
  12. Zucker I and Beery AK (2010) Males still dominate animal studies. Nature 465, 690 https://doi.org/10.1038/465690a
  13. Kong BY, Haugh IM, Schlosser BJ, Getsios S and Paller AS (2016) Mind the Gap: Sex Bias in Basic Skin Research. J Invest Dermatol 136, 12-14 https://doi.org/10.1038/JID.2015.298
  14. Zakiniaeiz Y, Cosgrove KP, Potenza MN and Mazure CM (2016) Balance of the Sexes: Addressing Sex Differences in Preclinical Research. Yale J Biol Med 89, 255-259
  15. Klein SL (2012) Immune cells have sex and so should journal articles. Endocrinology 153, 2544-2550 https://doi.org/10.1210/en.2011-2120
  16. Deasy BM, Lu A, Tebbets JC et al (2007) A role for cell sex in stem cell-mediated skeletal muscle regeneration: female cells have higher muscle regeneration efficiency. J Cell Biol 177, 73-86 https://doi.org/10.1083/jcb.200612094
  17. Penaloza C, Estevez B, Orlanski S et al (2009) Sex of the cell dictates its response: differential gene expression and sensitivity to cell death inducing stress in male and female cells. FASEB J 23, 1869-1879 https://doi.org/10.1096/fj.08-119388
  18. Taylor KE, Vallejo-Giraldo C, Schaible NS, Zakeri R and Miller VM (2011) Reporting of sex as a variable in cardiovascular studies using cultured cells. Biol Sex Differ 2, 11 https://doi.org/10.1186/2042-6410-2-11
  19. Shah K, McCormack CE and Bradbury NA (2014) Do you know the sex of your cells? Am J Physiol Cell Physiol 306, C3-18 https://doi.org/10.1152/ajpcell.00281.2013
  20. Park MN, Park JH, Paik HY and Lee SK (2015) Insufficient sex description of cells supplied by commercial vendors. Am J Physiol Cell Physiol 308, C578-580 https://doi.org/10.1152/ajpcell.00396.2014
  21. AG Gender position paper 2018-2020 (availabe at http://ec.europa.eu/transparency/regexpert/index.cfm?do=groupDetail.groupDetailDoc&id=28824&no=1.pdf).
  22. Duchesne A, Tannenbaum C and Einstein G (2017) Funding agency mechanisms to increase sex and gender analysis. The Lancet 389, 699
  23. Clayton JA and Collins FS (2014) Policy: NIH to balance sex in cell and animal studies. Nature 509, 282-283 https://doi.org/10.1038/509282a
  24. Tannenbaum C, Schwarz JM, Clayton JA, de Vries GJ and Sullivan C (2016) Evaluating sex as a biological variable in preclinical research: the devil in the details. Biol Sex Differ 7, 13 https://doi.org/10.1186/s13293-016-0066-x
  25. De Castro P, Heidari S and Babor TF (2016) Sex And Gender Equity in Research (SAGER): reporting guidelines as a framework of innovation for an equitable approach to gender medicine. Commentary. Ann Ist Super Sanita 52, 154-157
  26. Kilkenny C, Browne WJ, Cuthill IC, Emerson M and Altman DG (2010) Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol 8, e1000412 https://doi.org/10.1371/journal.pbio.1000412
  27. Prager EM (2017) Addressing sex as a biological variable. J Neurosci Res 95, 11 https://doi.org/10.1002/jnr.23979
  28. Fields RD (2014) NIH policy: mandate goes too far. Nature 510, 340
  29. Sandberg K, Verbalis JG, Yosten GL and Samson WK (2014) Sex and basic science. A Title IX position. Am J Physiol Regul Integr Comp Physiol 307, R361-365 https://doi.org/10.1152/ajpregu.00251.2014
  30. McCullough LD, de Vries GJ, Miller VM, Becker JB, Sandberg K and McCarthy MM (2014) NIH initiative to balance sex of animals in preclinical studies: generative questions to guide policy, implementation, and metrics. Biol Sex Differ 5, 15 https://doi.org/10.1186/s13293-014-0015-5
  31. Sandberg K, Umans JG and Georgetown Consensus Conference Work Group (2015) Recommendations concerning the new U.S. National Institutes of Health initiative to balance the sex of cells and animals in preclinical research. FASEB J 29, 1646-1652 https://doi.org/10.1096/fj.14-269548
  32. Wald C and Wu C (2010) Biomedical research. Of mice and women: the bias in animal models. Science 327, 1571-1572 https://doi.org/10.1126/science.327.5973.1571
  33. Prendergast BJ, Onishi KG and Zucker I (2014) Female mice liberated for inclusion in neuroscience and biomedical research. Neurosci Biobehav Rev 40, 1-5 https://doi.org/10.1016/j.neubiorev.2014.01.001
  34. Becker JB, Arnold AP, Berkley KJ et al (2005) Strategies and methods for research on sex differences in brain and behavior. Endocrinology 146, 1650-1673 https://doi.org/10.1210/en.2004-1142
  35. Khosla S, Amin S and Orwoll E (2008) Osteoporosis in men. Endocr Rev 29, 441-464 https://doi.org/10.1210/er.2008-0002