Abstract
Polycystic ovary syndrome (PCOS) is a prevalent condition in women of reproductive age. PCOS is characterized by androgen excess and chronic anovulation and associated with low-grade inflammation and metabolic comorbidities. Some trace elements have been linked to pathophysiological mechanisms of oxidative stress and inflammation in different disorders. Therefore, we conducted a systematic review and meta-analysis of the available evidence regarding trace element concentrations in PCOS. We reviewed MEDLINE and EMBASE in search of case-control, cross-sectional, and cohort studies published until September 2015. Of 183 studies identified, six were selected for systematic review. All used the Rotterdam criteria for the diagnosis of PCOS. Two studies evaluating chromium and one assessing cobalt levels did not observe differences between PCOS and controls. Another study recorded similar nickel and vanadium levels between the groups, but lower selenium concentrations in women with PCOS compared to controls. Four studies were included in the random effects model meta-analysis, for a total of 264 PCOS and 151 control women. Copper levels were found to be higher in women with PCOS than in controls [mean difference 0.12 ppm (95 % CI 0.07; 0.17 ppm); I 2 = 0 %]. Manganese [mean difference 0.04 ppm (95 % CI −0.05; 0.13 ppm); I 2 = 94.4 %] and zinc concentrations [mean difference 0.02 ppm (95 % CI −0.12; 0.16 ppm); I 2 = 92.4 %] were similar between the groups. The present results suggest a relationship between increased copper concentration and PCOS. This systematic review and meta-analysis is registered in PROSPERO under number CRD42016034036.
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March WA, Moore VM, Willson KJ, Phillips DI, Norman RJ, Davies MJ (2010) The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod 25:544–551. doi:10.1093/humrep/dep399
Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group (2004) Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 81:19–25. doi:10.1016/j.fertnstert.2003.10.004
Goverde AJ, van Koert AJ, Eijkemans MJ, Knauff EA, Westerveld HE, Fauser BC, Broekmans FJ (2009) Indicators for metabolic disturbances in anovulatory women with polycystic ovary syndrome diagnosed according to the Rotterdam consensus criteria. Hum Reprod 24:710–717. doi:10.1093/humrep/den433
Wild RA, Carmina E, Diamanti-Kandarakis E, Dokras A, Escobar-Morreale HF, Futterweit W, Lobo R, Norman RJ, Talbott E, Dumesic DA (2010) Assessment of cardiovascular risk and prevention of cardiovascular disease in women with the polycystic ovary syndrome: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society. J Clin Endocrinol Metab 95:2038–2049. doi:10.1210/jc.2009-2724
Spritzer PM, Lecke SB, Satler F, Morsch DM (2015) Adipose tissue dysfunction, adipokines, and low-grade chronic inflammation in polycystic ovary syndrome. Reproduction 149:R219–227. doi:10.1530/REP-14-0435
Wiltgen D, Spritzer PM (2010) Variation in metabolic and cardiovascular risk in women with different polycystic ovary syndrome phenotypes. Fertil Steril 94:2493–2496. doi:10.1016/j.fertnstert.2010.02.015
Jones MR, Chua AK, Mengesha EA, Taylor KD, Chen YD, Li X, Krauss RM, Rotter JI, Network RM, Legro RS, Azziz R, Goodarzi MO (2012) Metabolic and cardiovascular genes in polycystic ovary syndrome: a candidate-wide association study (CWAS). Steroids 77:317–322. doi:10.1016/j.steroids.2011.12.005
Murri M, Luque-Ramírez M, Insenser M, Ojeda-Ojeda M, Escobar-Morreale HF (2013) Circulating markers of oxidative stress and polycystic ovary syndrome (PCOS): a systematic review and meta-analysis. Hum Reprod Update 19:268–288. doi:10.1093/humupd/dms059
González F, Rote NS, Minium J, Kirwan JP (2006) Reactive oxygen species-induced oxidative stress in the development of insulin resistance and hyperandrogenism in polycystic ovary syndrome. J Clin Endocrinol Metab 91:336–340, http://dx.doi.org/10.1210/jc.2005-1696
González F, Sia CL, Shepard MK, Rote NS, Minium J (2012) Inflammation in response to glucose ingestion is independent of excess abdominal adiposity in normal-weight women with polycystic ovary syndrome. J Clin Endocrinol Metab 97:4071–4079. doi:10.1210/jc.2012-2131
Byrne C, Divekar SD, Storchan GB, Parodi DA, Martin MB (2013) Metals and breast cancer. J Mammary Gland Biol Neoplasia 18:63–73. doi:10.1007/s10911-013-9273-9
Meramat A, Rajab NF, Shahar S, Sharif R (2015) Cognitive impairment, genomic instability and trace elements. J Nutr Health Aging 19:48–57. doi:10.1007/s12603-014-0489-1
Saghiri MA, Asatourian A, Orangi J, Sorenson CM, Sheibani N (2015) Functional role of inorganic trace elements in angiogenesis—part I: N, Fe, Se, P, Au, and Ca. Crit Rev Oncol Hematol 96:129–142. doi:10.1016/j.critrevonc.2015.10.004
Vázquez M, Calatayud M, Jadán Piedra C, Chiocchetti GM, Vélez D, Devesa V (2015) Toxic trace elements at gastrointestinal level. Food Chem Toxicol 86:163–175. doi:10.1016/j.fct.2015.10.006
Malavolta M, Piacenza F, Basso A, Giacconi R, Costarelli L, Mocchegiani E (2015) Serum copper to zinc ratio: relationship with aging and health status. Mech Ageing Dev 151:93–100. doi:10.1016/j.mad.2015.01.004
Misra S, Boylan M, Selvam A, Spallholz JE, Björnstedt M (2015) Redox-active selenium compounds—from toxicity and cell death to cancer treatment. Nutrients 7:3536–3556. doi:10.3390/nu7053536
Hua Y, Clark S, Ren J, Srejayan N (2012) Molecular mechanisms of chromium in alleviating insulin resistance. J Nutr Biochem 23:313–319. doi:10.1016/j.jnutbio.2011.11.001
Zhou J, Xu H, Huang K (2016) Organoselenium small molecules and chromium(III) complexes for intervention in chronic low-grade inflammation and type 2 diabetes. Curr Top Med Chem 16:823–834. doi:10.2174/1568026615666150827094815
Clark TA, Deniset JF, Heyliger CE, Pierce GN (2014) Alternative therapies for diabetes and its cardiac complications: role of vanadium. Heart Fail Rev 19:123–132. doi:10.1007/s10741-013-9380-0
Cruz KJ, de Oliveira AR, Marreiro DN (2015) Antioxidant role of zinc in diabetes mellitus. World J Diabetes 6:333–337. doi:10.4239/wjd.v6.i2.333
Tajaddini MH, Keikha M, Razzazzadeh A, Kelishadi R (2015) A systematic review on the association of serum selenium and metabolic syndrome. J Res Med Sci 20:782–789. doi:10.4103/1735-1995.168403
Benstoem C, Goetzenich A, Kraemer S, Borosch S, Manzanares W, Hardy G, Stoppe C (2015) Selenium and its supplementation in cardiovascular disease—what do we know? Nutrients 7:3094–3118. doi:10.3390/nu7053094
Ganz T, Nemeth E (2015) Iron homeostasis in host defence and inflammation. Nat Rev Immunol 15:500–510. doi:10.1038/nri3863
Speisky H, Gómez M, Burgos-Bravo F, López-Alarcón C, Jullian C, Olea-Azar C, Aliaga ME (2009) Generation of superoxide radicals by copper-glutathione complexes: redox-consequences associated with their interaction with reduced glutathione. Bioorg Med Chem 17:1803–1810. doi:10.1016/j.bmc.2009.01.069
Catalani S, Rizzetti MC, Padovani A, Apostoli P (2012) Neurotoxicity of cobalt. Hum Exp Toxicol 31:421–437. doi:10.1177/0960327111414280
Zambelli B, Ciurli S (2013) Nickel and human health. Met Ions Life Sci 13:321–357. doi:10.1007/978-94-007-7500-8_10
Baker MG, Simpson CD, Stover B, Sheppard L, Checkoway H, Racette BA, Seixas NS (2014) Blood manganese as an exposure biomarker: state of the evidence. J Occup Environ Hyg 11:210–217. doi:10.1080/15459624.2013.852280
Chen P, Chakraborty S, Mukhopadhyay S, Lee E, Paolieoo MM, Bowman AB, Aschner M (2015) Manganese homeostasis in the nervous system. J Neurochem 134:601–610. doi:10.1111/jnc.13170
Gruzewska K, Michno A, Pawelczyk T, Bielarczyk H (2014) Essentiality and toxicity of vanadium supplements in health and pathology. J Physiol Pharmacol 65:603–611
Ashoush S, Abou-Gamrah A, Bayoumy H, Othman N (2016) Chromium picolinate reduces insulin resistance in polycystic ovary syndrome: randomized controlled trial. J Obstet Gynaecol Res 42(3):279–85. doi:10.1111/jog.12907
Amooee S, Parsanezhad ME, Ravanbod Shirazi M, Alborzi S, Samsami A (2013) Metformin versus chromium picolinate in clomiphene citrate-resistant patients with PCOs: a double-blind randomized clinical trial. Iran J Reprod Med 11:611–618
Lydic ML, McNurlan M, Bembo S, Mitchell L, Komaroff E, Gelato M (2006) Chromium picolinate improves insulin sensitivity in obese subjects with polycystic ovary syndrome. Fertil Steril 86:243–246. doi:10.1016/j.fertnstert.2005.11.069
Lucidi RS, Thyer AC, Easton CA, Holden AE, Schenken RS, Brzyski RG (2005) Effect of chromium supplementation on insulin resistance and ovarian and menstrual cyclicity in women with polycystic ovary syndrome. Fertil Steril 84:1755–1757. doi:10.1016/j.fertnstert.2005.06.028
Jamilian M, Foroozanfard F, Bahmani F, Talaee R, Monavari M, Asemi Z (2015) Effects of zinc supplementation on endocrine outcomes in women with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial. Biol Trace Elem Res 170(2):271–8. doi:10.1007/s12011-015-0480-7
Jamilian M, Bahmani F, Siavashani MA, Mazloomi M, Asemi Z, Esmaillzadeh A (2015) The effects of chromium supplementation on endocrine profiles, biomarkers of inflammation, and oxidative stress in women with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial. Biol Trace Elem Res. doi:10.1007/s12011-015-0570-6
Jamilian M, Razavi M, Fakhrie Kashan Z, Ghandi Y, Baqherian T, Asemi Z (2015) Metabolic response to selenium supplementation in women with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial. Clin Endocrinol (Oxf) 82:885–891. doi:10.1111/cen.12699
Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol 62:e1–34. doi:10.1016/j.jclinepi.2009.06.006
Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, Moher D, Becker BJ, Sipe TA, Thacker SB (2000) Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 283:2008–2012. doi:10.1001/jama.283.15.2008
Wells G, Shea B, O'Connell D et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp, 2015.
Martínez-García MA, Luque-Ramírez M, San-Millán JL, Escobar-Morreale HF (2009) Body iron stores and glucose intolerance in premenopausal women: role of hyperandrogenism, insulin resistance, and genomic variants related to inflammation, oxidative stress, and iron metabolism. Diabetes Care 32:1525–1530. doi:10.2337/dc09-0420
Escobar-Morreale HF, Luque-Ramírez M, Alvarez-Blasco F, Botella-Carretero JI, Sancho J, San Millán JL (2005) Body iron stores are increased in overweight and obese women with polycystic ovary syndrome. Diabetes Care 28:2042–2044, http://dx.doi.org/10.2337/diacare.28.8.2042
Zheng G, Wang L, Guo Z, Sun L, Wang L, Wang C, Zuo Z, Qiu H (2015) Association of serum heavy metals and trace element concentrations with reproductive hormone levels and polycystic ovary syndrome in a Chinese population. Biol Trace Elem Res 167:1–10. doi:10.1007/s12011-015-0294-7
Guler I, Himmetoglu O, Turp A, Erdem A, Erdem M, Onan MA, Taskiran C, Taslipinar MY, Guner H (2014) Zinc and homocysteine levels in polycystic ovarian syndrome patients with insulin resistance. Biol Trace Elem Res 158:297–304. doi:10.1007/s12011-014-9941-7
Coskun A, Arikan T, Kilinc M, Arikan DC, Ekerbiçer HÇ (2013) Plasma selenium levels in Turkish women with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol 168:183–186. doi:10.1016/j.ejogrb.2013.01.021
Celik C, Bastu E, Abali R, Alpsoy S, Guzel EC, Aydemir B, Yeh J (2013) The relationship between copper, homocysteine and early vascular disease in lean women with polycystic ovary syndrome. Gynecol Endocrinol 29:488–491. doi:10.3109/09513590.2013.774361
Chakraborty P, Ghosh S, Goswami SK, Kabir SN, Chakravarty B, Jana K (2013) Altered trace mineral milieu might play an aetiological role in the pathogenesis of polycystic ovary syndrome. Biol Trace Elem Res 152:9–15. doi:10.1007/s12011-012-9592-5
Kurdoglu Z, Kurdoglu M, Demir H, Sahin HB (2012) Serum trace elements and heavy metals in polycystic ovary syndrome. Hum Exp Toxicol 31:452–456. doi:10.1177/0960327111424299
Sabuncu T, Vural H, Harma M, Harma M (2001) Oxidative stress in polycystic ovary syndrome and its contribution to the risk of cardiovascular disease. Clin Biochem 34:407–413. doi:10.1016/S0009-9120(01)00245-4
Fenkci V, Fenkci S, Yilmazer M, Serteser M (2003) Decreased total antioxidant status and increased oxidative stress in women with polycystic ovary syndrome may contribute to the risk of cardiovascular disease. Fertil Steril 80:123–127. doi:10.1016/S0015-0282(03)00571-5
Uchida Y, Ohba K, Yoshioka T, Irie K, Muraki T, Maru Y (2004) Cellular carbonyl stress enhances the expression of plasminogen activator inhibitor-1 in rat white adipocytes via reactive oxygen species-dependent pathway. J Biol Chem 279:4075–4083. doi:10.1074/jbc.M304222200
Taylor CG (2005) Zinc, the pancreas, and diabetes: insights from rodent studies and future directions. Biometals 18:305–312. doi:10.1007/s10534-005-3686-x
Stamatiadis D, Bulteau-Portois MC, Mowszowicz I (1988) Inhibition of 5 alpha-reductase activity in human skin by zinc and azelaic acid. Br J Dermatol 119:627–632. doi:10.1111/j.1365-2133.1988.tb03474.x
Ansar S, Alhefdhi T, Aleem AM (2015) Status of trace elements and antioxidants in premenopausal and postmenopausal phase of life: a comparative study. Int J Clin Exp Med 8:19486–19490
Rains JL, Jain SK (2011) Oxidative stress, insulin signaling, and diabetes. Free Radic Biol Med 50:567–575. doi:10.1016/j.freeradbiomed.2010.12.006
Yin RV, Phung OJ (2015) Effect of chromium supplementation on glycated hemoglobin and fasting plasma glucose in patients with diabetes mellitus. Nutr J 14:14. doi:10.1186/1475-2891-14-14
Tian H, Guo X, Wang X, He Z, Sun R, Ge S, Zhang Z (2013) Chromium picolinate supplementation for overweight or obese adults. Cochrane Database Syst Rev 11, CD010063. doi:10.1002/14651858.CD010063.pub2
Jomova K, Valko M (2011) Advances in metal-induced oxidative stress and human disease. Toxicology 283:65–87. doi:10.1016/j.tox.2011.03.001
Galanis A, Karapetsas A, Sandaltzopoulos R (2009) Metal-induced carcinogenesis, oxidative stress and hypoxia signalling. Mutat Res 674:31–35. doi:10.1016/j.mrgentox.2008.10.008
Chen YW, Yang CY, Huang CF, Hung DZ, Leung YM, Liu SH (2009) Heavy metals, islet function and diabetes development. Islets 1:169–176. doi:10.4161/isl.1.3.9262
Liu G, Sun L, Pan A, Zhu M, Li Z, Zhenzhenwang Z, Liu X, Ye X, Li H, Zheng H, Ong CN, Yin H, Lin X, Chen Y (2015) Nickel exposure is associated with the prevalence of type 2 diabetes in Chinese adults. Int J Epidemiol 44:240–248. doi:10.1093/ije/dyu200
Flores CR, Puga MP, Wrobel K, Garay Sevilla ME, Wrobel K (2011) Trace elements status in diabetes mellitus type 2: possible role of the interaction between molybdenum and copper in the progress of typical complications. Diabetes Res Clin Pract 91:333–341. doi:10.1016/j.diabres.2010.12.014
Saghiri MA, Orangi J, Asatourian A, Sorenson CM, Sheibani N (2016) Functional role of inorganic trace elements in angiogenesis part III: (Ti, Li, Ce, As, Hg, Va, Nb and Pb). Crit Rev Oncol Hematol 98:290–301. doi:10.1016/j.critrevonc.2015.10.004
McNaught AD, Wilkinson A (1997) Compendium of chemical terminology. The Gold Book, London
Niekraszewicz LAB, de Souza CT, Stori EM, Jobim PFC, Amaral L, Dias JF (2015) The role of micro-NRA and micro-PIXE in carbon mapping of organic tissue. Nucl Instrum Meth Phys Res Section B Beam Interact Materials Atoms 348:160–164. doi:10.1016/j.nimb.2015.01.023
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This work was supported by grants from Brazilian National Institute of Hormones and Women’s Health/Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq INCT 573747/20083), Brazil. The funding sources had no influence in the writing or decision to submit the article for publication.
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Spritzer, P.M., Lecke, S.B., Fabris, V.C. et al. Blood Trace Element Concentrations in Polycystic Ovary Syndrome: Systematic Review and Meta-analysis. Biol Trace Elem Res 175, 254–262 (2017). https://doi.org/10.1007/s12011-016-0774-4
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DOI: https://doi.org/10.1007/s12011-016-0774-4