Abstract
Introduction
Alopecia areata is a well-known autoimmune disease affecting humans. Polyamines are closely associated with proliferation and inflammation, and steroid hormones are involved in immune responses. Additionally, bile acids play roles in immune homeostasis by activating various signaling pathways; however, the roles of these substances and their metabolites in alopecia areata remain unclear.
Objectives
In this study, we aimed to identify differences in metabolite levels in urine samples from patients with alopecia areata and healthy controls.
Methods
To assess polyamine, androgen, and bile acid concentrations, we performed high-performance liquid chromatography–tandem mass spectrometry.
Results
Our results showed that spermine and dehydroepiandrosterone levels differed significantly between male patients and controls, whereas ursodeoxycholic acid levels were significantly higher in female patients with alopecia areata than in controls.
Conclusion
Our findings suggested different urinary polyamine, androgen, and bile acid concentrations between alopecia areata patients and normal controls. Additionally, levels of endogenous substances varied according to sex, and this should be considered when developing appropriate treatments and diagnostic techniques. Our findings improve our understanding of polyamine, androgen, and bile acid profiles in patients with alopecia areata and highlight the need to consider sex-related differences.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ahn, R. S., Lee, Y. J., Choi, J. Y., Kwon, H. B., & Chun, S. I. (2007). Salivary cortisol and DHEA levels in the Korean population: age-related differences, diurnal rhythm, and correlations with serum levels. Yonsei Medical Journal,48(3), 379–388. https://doi.org/10.3349/ymj.2007.48.3.379.
Amaral, J. D., Viana, R. J., Ramalho, R. M., Steer, C. J., & Rodrigues, C. M. (2009). Bile acids: regulation of apoptosis by ursodeoxycholic acid. Journal of Lipid Research,50(9), 1721–1734. https://doi.org/10.1194/jlr.R900011-JLR200.
Bang, H. J., Yang, Y. J., Lho, D. S., Lee, W. Y., Sim, W. Y., & Chung, B. C. (2004). Comparative studies on level of androgens in hair and plasma with premature male-pattern baldness. Journal of Dermatological Science,34(1), 11–16.
Bendera, R., & Wilson, L. S. (2019). The regulatory effect of biogenic polyamines spermine and spermidine in men and women. Open Journal of Endocrine and Metabolic Diseases,9(03), 35.
Bodemer, C., Peuchmaur, M., Fraitaig, S., Chatenoud, L., Brousse, N., & De Prost, Y. (2000). Role of cytotoxic T cells in chronic alopecia areata. Journal of Investigative Dermatology,114(1), 112–116. https://doi.org/10.1046/j.1523-1747.2000.00828.x.
Brooks, W. H. (1995). Polyamine involvement in the cell cycle, apoptosis, and autoimmunity. Medical Hypotheses,44(5), 331–338.
Brooks, W. H. (2012). Autoimmune diseases and polyamines. Clinical Reviews in Allergy & Immunology,42(1), 58–70. https://doi.org/10.1007/s12016-011-8290-y.
Buyanova, S. M., Chistyakov, D. V., Astakhova, A. A., & Sergeeva, M. G. (2017). The effect of dehydroepiandrosterone on inflammatory response of astroglial cells. Biochemistry Moscow Supplement Series A: Membrane and Cell Biology,11(4), 304–310. https://doi.org/10.1134/s199074781704002x.
Byun, J. A., Lee, S. H., Jung, B. H., Choi, M. H., Moon, M. H., & Chung, B. C. (2008). Analysis of polyamines as carbamoyl derivatives in urine and serum by liquid chromatography–tandem mass spectrometry. Biomedical Chromatography,22(1), 73–80. https://doi.org/10.1002/bmc.898.
Calmus, Y., & Poupon, R. (2014). Shaping macrophages function and innate immunity by bile acids: Mechanisms and implication in cholestatic liver diseases. Clinics and Research in Hepatology and Gastroenterology,38(5), 550–556. https://doi.org/10.1016/j.clinre.2014.07.007.
Chavez-Talavera, O., Tailleux, A., Lefebvre, P., & Staels, B. (2017). Bile acid control of metabolism and inflammation in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic fatty liver disease. Gastroenterology,152(7), 1679–1694. https://doi.org/10.1053/j.gastro.2017.01.055.
Cheng, M. L., Shiao, M. S., Chiu, D. T., Weng, S. F., Tang, H. Y., & Ho, H. Y. (2011). Biochemical disorders associated with antiproliferative effect of dehydroepiandrosterone in hepatoma cells as revealed by LC-based metabolomics. Biochemical Pharmacology,82(11), 1549–1561. https://doi.org/10.1016/j.bcp.2011.07.104.
Cho, H. J., Kim, J. D., Lee, W. Y., Chung, B. C., & Choi, M. H. (2009). Quantitative metabolic profiling of 21 endogenous corticosteroids in urine by liquid chromatography-triple quadrupole-mass spectrometry. Analytica Chimica Acta,632(1), 101–108. https://doi.org/10.1016/j.aca.2008.10.059.
Choi, M. H., Yoo, Y. S., & Chung, B. C. (2001). Biochemical roles of testosterone and epitestosterone to 5 alpha-reductase as indicators of male-pattern baldness. Journal of Investigative Dermatology,116(1), 57–61. https://doi.org/10.1046/j.1523-1747.2001.00188.x.
Choi, M. H., Moon, J. Y., Cho, S. H., Chung, B. C., & Lee, E. J. (2011). Metabolic alteration of urinary steroids in pre- and post-menopausal women, and men with papillary thyroid carcinoma. BMC Cancer,11, 342. https://doi.org/10.1186/1471-2407-11-342.
Cutolo, M., Sulli, A., Capellino, S., Villaggio, B., Montagna, P., Seriolo, B., et al. (2004). Sex hormones influence on the immune system: basic and clinical aspects in autoimmunity. Lupus,13(9), 635–638. https://doi.org/10.1191/0961203304lu1094oa.
Facchini, A., Borzi, R. M., Olivotto, E., Platano, D., Pagani, S., Cetrullo, S., et al. (2012). Role of polyamines in hypertrophy and terminal differentiation of osteoarthritic chondrocytes. Amino Acids,42(2–3), 667–678. https://doi.org/10.1007/s00726-011-1041-9.
Ferioli, M. E., Pinotti, O., & Pirona, L. (1999). Gender-related differences in polyamine oxidase activity in rat tissues. Amino Acids,17(2), 139–148.
Fiorucci, S., Biagioli, M., Zampella, A., & Distrutti, E. (2018). Bile acids activated receptors regulate innate immunity. Frontiers in Immunology,9, 1853. https://doi.org/10.3389/fimmu.2018.01853.
Furie, R. (2000). Dehydroepiandrosterone and biologics in the treatment of systemic lupus erythematosus. Current Rheumatology Reports,2(1), 44–50.
Gilhar, A., Etzioni, A., & Paus, R. (2012). Alopecia areata. New England Journal of Medicine,366(16), 1515–1525. https://doi.org/10.1056/NEJMra1103442.
Gonzalez-Montelongo, M. C., Marin, R., Perez, J. A., Gomez, T., & Diaz, M. (2013). Polyamines transduce the nongenomic, androgen-induced calcium sensitization in intestinal smooth muscle. Molecular Endocrinology,27(10), 1603–1616. https://doi.org/10.1210/me.2013-1201.
Gustafsson, J. E., & Uzqueda, H. R. (1978). The influence of citrate and phosphate on the Mancini single radial immunodiffusion technique and suggested improvements for the determination of urinary albumin. Clinica Chimica Acta,90(3), 249–257. https://doi.org/10.1016/0009-8981(78)90264-4.
Hazeldine, J., Arlt, W., & Lord, J. M. (2010). Dehydroepiandrosterone as a regulator of immune cell function. Journal of Steroid Biochemistry and Molecular Biology,120(2–3), 127–136. https://doi.org/10.1016/j.jsbmb.2009.12.016.
Hedlund, E., Gustafsson, J. A., & Warner, M. (2001). Cytochrome P450 in the brain; a review. Current Drug Metabolism,2(3), 245–263.
Hedman, M., Nilsson, E., & de la Torre, B. (1992). Low blood and synovial fluid levels of sulpho-conjugated steroids in rheumatoid arthritis. Clinical and Experimental Rheumatology,10(1), 25–30.
Im, E., Lew, B. L., Lee, M. Y., Lee, J., Paeng, K. J., & Chung, B. C. (2019). Simultaneous determination of androgens and prostaglandins in human urine using ultra-high-performance liquid chromatography–tandem mass spectrometry. Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences,1109, 45–53. https://doi.org/10.1016/j.jchromb.2019.01.022.
Kavathia, N., Jain, A., Walston, J., Beamer, B. A., & Fedarko, N. S. (2009). Serum markers of apoptosis decrease with age and cancer stage. Aging,1(7), 652–663. https://doi.org/10.18632/aging.100069.
Kim, M. J., & Suh, D. J. (1986). Profiles of serum bile acids in liver diseases. Korean Journal of Internal Medicine,1(1), 37–42. https://doi.org/10.3904/kjim.1986.1.1.37.
Kim, H. A., Lee, H. S., Shin, T. H., Jung, J. Y., Baek, W. Y., Park, H. J., et al. (2018). Polyamine patterns in plasma of patients with systemic lupus erythematosus and fever. Lupus,27(6), 930–938. https://doi.org/10.1177/0961203317751860.
Kumar, B. S., Chung, B. C., Lee, Y. J., Yi, H. J., Lee, B. H., & Jung, B. H. (2011). Gas chromatography–mass spectrometry-based simultaneous quantitative analytical method for urinary oxysterols and bile acids in rats. Analytical Biochemistry,408(2), 242–252. https://doi.org/10.1016/j.ab.2010.09.031.
Lee, N. K., Skinner, J. P., Zajac, J. D., & MacLean, H. E. (2011). Ornithine decarboxylase is upregulated by the androgen receptor in skeletal muscle and regulates myoblast proliferation. American Journal of Physiology: Endocrinology and Metabolism,301(1), E172–179. https://doi.org/10.1152/ajpendo.00094.2011.
Lee, Y. R., Lee, J., Lew, B. L., Sim, W. Y., Hong, J., & Chung, B. C. (2019a). Distribution of polyamines may be altered in different scalp regions of patients with hair loss. Experimental Dermatology,28(9), 1083–1086. https://doi.org/10.1111/exd.13998.
Lee, Y. R., Lew, B. L., Sim, W. Y., Lee, J., Hong, J., & Chung, B. C. (2019b). Altered polyamine profiling in the hair of patients with androgenic alopecia and alopecia areata. Journal of Dermatology,46(11), 985–992. https://doi.org/10.1111/1346-8138.15063.
Li, Y., Tang, R., Leung, P. S. C., Gershwin, M. E., & Ma, X. (2017). Bile acids and intestinal microbiota in autoimmune cholestatic liver diseases. Autoimmunity Reviews,16(9), 885–896. https://doi.org/10.1016/j.autrev.2017.07.002.
Moon, J. Y., Kwon, W., Suh, S., Cheong, J. C., In, M. K., Chung, B. C., et al. (2014). Reference ranges for urinary levels of testosterone and epitestosterone, which may reveal gonadal function, in a Korean male population. Journal of Steroid Biochemistry and Molecular Biology,140, 100–105. https://doi.org/10.1016/j.jsbmb.2013.12.001.
Moulton, V. R. (2018). Sex hormones in acquired immunity and autoimmune disease. Frontiers in Immunology,9, 2279. https://doi.org/10.3389/fimmu.2018.02279.
Nakamura, K., Yoneda, M., Yokohama, S., Tamori, K., Sato, Y., Aso, K., et al. (1998). Efficacy of ursodeoxycholic acid in Japanese patients with type 1 autoimmune hepatitis. Journal of Gastroenterology and Hepatology,13(5), 490–495.
Orentreich, N., Brind, J. L., Rizer, R. L., & Vogelman, J. H. (1984). Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. Journal of Clinical Endocrinology and Metabolism,59(3), 551–555. https://doi.org/10.1210/jcem-59-3-551.
Palaszynski, K. M., Loo, K. K., Ashouri, J. F., Liu, H. B., & Voskuhl, R. R. (2004). Androgens are protective in experimental autoimmune encephalomyelitis: Implications for multiple sclerosis. Journal of Neuroimmunology,146(1–2), 144–152.
Pillai, R. B., Tolia, V., Rabah, R., Simpson, P. M., Vijesurier, R., & Lin, C. H. (1999). Increased colonic ornithine decarboxylase activity in inflammatory bowel disease in children. Digestive Diseases and Sciences,44(8), 1565–1570.
Pirinen, E., Gylling, H., Itkonen, P., Yaluri, N., Heikkinen, S., Pietila, M., et al. (2010). Activated polyamine catabolism leads to low cholesterol levels by enhancing bile acid synthesis. Amino Acids,38(2), 549–560. https://doi.org/10.1007/s00726-009-0416-7.
Pratt, C. H., King, L. E., Jr., Messenger, A. G., Christiano, A. M., & Sundberg, J. P. (2017). Alopecia areata. Nature Reviews Disease Primers,3, 17011. https://doi.org/10.1038/nrdp.2017.11.
Ryu, H. K., Kim, K. M., Yoo, E. A., Sim, W. Y., & Chung, B. C. (2006). Evaluation of androgens in the scalp hair and plasma of patients with male-pattern baldness before and after finasteride administration. British Journal of Dermatology,154(4), 730–734. https://doi.org/10.1111/j.1365-2133.2005.07072.x.
Silva, M. A., Klafke, J. Z., Rossato, M. F., Gewehr, C., Guerra, G. P., Rubin, M. A., et al. (2011). Role of peripheral polyamines in the development of inflammatory pain. Biochemical Pharmacology,82(3), 269–277. https://doi.org/10.1016/j.bcp.2011.04.015.
Soulet, D., & Rivest, S. (2003). Polyamines play a critical role in the control of the innate immune response in the mouse central nervous system. Journal of Cell Biology,162(2), 257–268. https://doi.org/10.1083/jcb.200301097.
Steinberg, A. D., Melez, K. A., Raveche, E. S., Reeves, J. P., Boegel, W. A., Smathers, P. A., et al. (1979). Approach to the study of the role of sex hormones in autoimmunity. Arthritis & Rheumatism,22(11), 1170–1176.
Straub, R. H., Vogl, D., Gross, V., Lang, B., Scholmerich, J., & Andus, T. (1998). Association of humoral markers of inflammation and dehydroepiandrosterone sulfate or cortisol serum levels in patients with chronic inflammatory bowel disease. American Journal of Gastroenterology,93(11), 2197–2202. https://doi.org/10.1111/j.1572-0241.1998.00535.x.
Takaba, H., & Takayanagi, H. (2017). The mechanisms of T cell selection in the thymus. Trends in Immunology,38(11), 805–816. https://doi.org/10.1016/j.it.2017.07.010.
Yukioka, K., Wakitani, S., Yukioka, M., Furumitsu, Y., Shichikawa, K., Ochi, T., et al. (1992). Polyamine levels in synovial tissues and synovial fluids of patients with rheumatoid arthritis. Journal of Rheumatology,19(5), 689–692.
Zhang, M., Caragine, T., Wang, H., Cohen, P. S., Botchkina, G., Soda, K., et al. (1997). Spermine inhibits proinflammatory cytokine synthesis in human mononuclear cells: A counterregulatory mechanism that restrains the immune response. Journal of Experimental Medicine,185(10), 1759–1768. https://doi.org/10.1084/jem.185.10.1759.
Zhang, M., Wang, H., & Tracey, K. J. (2000). Regulation of macrophage activation and inflammation by spermine: A new chapter in an old story. Critical Care Medicine,28(4 Suppl), N60–66.
Zhu, C., Fuchs, C. D., Halilbasic, E., & Trauner, M. (2016a). Bile acids in regulation of inflammation and immunity: Friend or foe? Clinical and Experimental Rheumatology,34(4 Suppl 98), 25–31.
Zhu, M. L., Bakhru, P., Conley, B., Nelson, J. S., Free, M., Martin, A., et al. (2016b). Sex bias in CNS autoimmune disease mediated by androgen control of autoimmune regulator. Nature Communications,7, 11350. https://doi.org/10.1038/ncomms11350.
Acknowledgements
This study was supported by a grant from the Korea Institute of Science and Technology Institutional Program (Grant No. 2E29290).
Author information
Authors and Affiliations
Contributions
YRL and HK wrote the manuscript and performed the experiments. BLL and WYS contributed to the collection of essential samples. JL analyzed the data. HBO and JH designed the experiments. BCC supervised the research. All authors approved the final version of the manuscript.
Corresponding authors
Ethics declarations
Conflict of interest
All authors declare that they have no conflict of interest.
Ethical approval
All procedures performed in studies involving human participants were approved by the Ethics Committee of the Kyung Hee University Medical center at Gangdong and approved by the institutional review board (IRB No. 2016-11-037-007) and performed in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent
Written informed consent was obtained from all patients and controls prior to sample collection, and consent was obtained from a parent or legal guardian prior to participation by minors in this study.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Lee, Y.R., Kim, H., Lew, B.L. et al. Sex-related differences in urinary immune-related metabolic profiling of alopecia areata patients. Metabolomics 16, 15 (2020). https://doi.org/10.1007/s11306-020-1634-y
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s11306-020-1634-y