Abstract
The objective of this study is to explore the correlation of metal levels with assisted reproductive technology (ART) outcomes in polycystic ovary syndrome (PCOS) patients. The individuals were recruited who met the research criteria, only tubal factor or male infertility served as the control group (n = 40) and patient group was PCOS patients (n = 35). Individuals (n = 75) were divided into PCOS group (n = 35) and control group (n = 40). The normal body mass index (BMI) group (control) includes women with BMI < 25 kg/m2 in PCOS group (n = 24) and control group (n = 33), and BMI ≥ 25 kg/m2 in PCOS group (n = 11) and control group (n = 7). We performed an analysis of insulin resistance (IR) (n = 15) group and without insulin resistance (NIR) group (n = 20) in PCOS patient and control patients. Comparing difference demographic data, ART outcomes and the metal levels in every group respectively, the correlation of metal levels and ART outcomes in control participants and PCOS patients were analyzed by the Spearman correlation analysis, and multiple linear regression model was used to examine the association between the concentration of 19 metals and ART outcomes in PCOS group and control group. Plasma manganese (Mn), titanium (Ti), sodium (Na), magnesium (Mg), copper (Cu), calcium (Ca)/Mg ratio, and Cu/zinc (Zn) ratio levels in PCOS patients were higher than that in control, while Zn and Ca levels were lower in PCOS patients than that in control. The Mg levels had a positive connection with the number of eggs recovered, and the iron (Fe) levels were positively associated with the number of transplanted embryos in PCOS-IR. In PCOS-NIR, Mn levels positively correlated with the number of follicles and the number of good embryos. Silver (Ag) levels were negatively correlated with the number of follicles, and aluminum (Al) levels were negatively related with the normal fertilization and the number of good embryos. The Spearman analysis in PCOS-BMI ≥ 25 group exhibited that nickel (Ni) levels were negatively associated with the number of follicles. The plasma metal levels seem to affect the clinical manifestations and in vitro fertilization outcomes in assisted reproduction.
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs12011-024-04085-9/MediaObjects/12011_2024_4085_Fig1_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs12011-024-04085-9/MediaObjects/12011_2024_4085_Fig2_HTML.png)
Similar content being viewed by others
Data Availability
The datasets analyzed during the current study could be available from the corresponding author on reasonable request.
Abbreviations
- PCOS:
-
Polycystic ovary syndrome
- BMI:
-
Body mass index
- IR:
-
Insulin resistance
- IVF:
-
In vitro fertility
- ART:
-
Assisted reproductive technology
- FBG:
-
Fasting blood glucose
- FSH:
-
Follicle-stimulating hormone
- LH:
-
Luteinizing hormone
- P:
-
Progestogens
- T:
-
Testosterone
- E2 :
-
Estradiol
- AMH:
-
Anti-Mü-llerian hormon
- TSH:
-
Thyrotropin
- Total amount of GN:
-
Total amount of gonadotropins
- HCG:
-
Human chorionic gonadotropin
- GN days:
-
Gonadotropins days
- HOMA-IR:
-
Homeostatic model assessment insulin resistance index
- FINS:
-
Fasting insulin concentration
- SD:
-
Standard deviation
- hs-CRP:
-
Hypersensitive-c-reactive-protein
- TAC:
-
Total antioxidant capacity
- MnSOD:
-
Manganese superoxide dismutase
- ROS:
-
Reactive oxygen species
- ATP:
-
Adenosine-triphosphate
- MMP:
-
Metalloproteinases
- OA:
-
Osteoarthritis
- CHD:
-
Coronary heart disease
- NO:
-
Nitric oxide
- Sn:
-
Tin
- Zn :
-
Zinc
- B:
-
Boron
- Cd:
-
Cadmium
- Pb:
-
Lead
- Ni:
-
Nickel
- Ba:
-
Barium
- Mn:
-
Manganese
- Fe:
-
Iron
- Cr:
-
Chromium
- Mg:
-
Magnesium
- Ga:
-
Gallium
- Ca:
-
Calcium
- Cu:
-
Copper
- Ti:
-
Titanium
- Ag:
-
Silver
- Al:
-
Aluminum
- Na:
-
Sodium
- K:
-
Kalium
References
Pokorska-Niewiada K, Brodowska A, Szczuko M (2021) The content of minerals in the PCOS group and the correlation with the parameters of metabolism. Nutrients 13(7):2214
Ullah A, Jahan S, Razak S et al (2017) Protective effects of GABA against metabolic and reproductive disturbances in letrozole induced polycystic ovarian syndrome in rats. J Ovarian Res 10(1):62
Tso LO, Costello MF, Albuquerque LET, Andriolo RB, Macedo CR (2020) Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome. Cochrane Database Syst Rev 12(12):CD006105
Kirmizi DA, Baser E, Turksoy VA et al (2020) Are heavy metal exposure and trace element levels related to metabolic and endocrine problems in polycystic ovary syndrome? Biol Trace Elem Res 198(1):77–86
Kim K, Pollack AZ, Nobles CJ et al (2021) Associations between blood cadmium and endocrine features related to PCOS-phenotypes in healthy women of reproductive age: a prospective cohort study. Environ Health 20(1):64
Ganz T, Nemeth E (2015) Iron homeostasis in host defence and inflammation. Nat Rev Immunol 15(8):500–510
Farsinejad-Marj M, Azadbakht L, Mardanian F et al (2020) Clinical and metabolic responses to magnesium supplementation in women with polycystic ovary syndrome. Biol Trace Elem Res 196(2):349–358
Kanafchian M, Esmaeilzadeh S, Mahjoub S et al (2020) Status of serum copper, magnesium, and total antioxidant capacity in patients with polycystic ovary syndrome. Biol Trace Elem Res 193(1):111–117
Tchounwou PB, Yedjou CG, Patlolla AK et al (2012) Heavy metal toxicity and the environment. Exp Suppl 101:133–164
Zhang X, Zhong T, Liu L et al (2015) Impact of soil heavy metal pollution on food safety in China. PLoS ONE 10(8):e0135182
Zhou Z, Peng C, Liu X et al (2022) Pollution and risk assessments of heavy metal(loid)s in the soil around lead-zinc smelteries via data integration analysis. Int J Environ Res Public Health 19(15):9698
UN Habitat and WHO. Progress on wastewater treatment: global status and acceleration needs for SDG indicator 6.3.1[EB/OL]. https://unhabitat.org/sites/default/files/2021/08/sdg6_indicator_report_631_progress_on_wastewater_treatment_2021_english_pages.pdf, accessed 4 May 2022.
Tolunay HE, Sukur YE, Ozkavukcu S et al (2016) Heavy metal and trace element concentrations in blood and follicular fluid affect ART outcome. Eur J Obstet Gynecol Reprod Biol 198:73–77
Aquino NB, Sevigny MB, Sabangan J et al (2012) The role of cadmium and nickel in estrogen receptor signaling and breast cancer: metalloestrogens or not? J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 30(3):189–224
Lai XL, **ong WJ, Li LS et al (2023) Zinc deficiency compromises the maturational competence of porcine oocyte by inducing mitophagy and apoptosis. Ecotoxicol Environ Saf 252:114593
Wang Q, Sun Y, Zhao A et al (2023) High dietary copper intake induces perturbations in the gut microbiota and affects host ovarian follicle development. Ecotoxicol Environ Saf 255:114810
Pokorska-Niewiada K, Brodowska A, Brodowski J et al (2022) Levels of trace elements in erythrocytes as endocrine disruptors in obese and nonobese women with polycystic ovary syndrome. Int J Environ Res Public Health 19(2):976
La Marca A, Sighinolfi G, Radi D et al (2010) Anti-Mullerian hormone (AMH) as a predictive marker in assisted reproductive technology (ART). Hum Reprod Update 16(2):113–130
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 (PCOS). Hum Reprod 19(1):41–47
Shokrpour M, Asemi Z (2019) The effects of magnesium and vitamin E co-supplementation on hormonal status and biomarkers of inflammation and oxidative stress in women with polycystic ovary syndrome. Biol Trace Elem Res 191(1):54–60
Lin J, Lin X, Qiu J et al (2023) Association between heavy metals exposure and infertility among American women aged 20–44 years: a cross-sectional analysis from 2013 to 2018 NHANES data. Front Public Health 11:1122183
Wu Y, Yang R, Lan J et al (2023) Iron overload modulates follicular microenvironment via ROS/HIF-1α/FSHR signaling. Free Radic Biol Med 196:37–52
Lakk-Bogáth D, Juraj NP, Meena BI et al (2021) Comparison of nonheme manganese- and iron-containing flavone synthase mimics. Molecules 26(11):3220
Kidir V, Uz E, Yigit A et al (2016) Manganese superoxide dismutase, glutathione peroxidase and catalase gene polymorphisms and clinical outcomes in acute kidney injury. Ren Fail 38(3):372–377
Faure C, Leveille P, Dupont C et al (2014) Are superoxide dismutase 2 and nitric oxide synthase polymorphisms associated with idiopathic infertility? Antioxid Redox Signal 21(4):565–569
Pournourali M, Tarang A, Haghighi SF et al (2016) Polymorphism variant of MnSOD A16V and risk of female infertility in northern Iran. Taiwan J Obstet Gynecol 55(6):801–803
Mckeating DR, Fisher JJ, Perkins AV (2019) Elemental metabolomics and pregnancy outcomes. Nutrients 11(1):565
Martinez-Finley EJ, Gavin CE, Aschner M et al (2013) Manganese neurotoxicity and the role of reactive oxygen species. Free Radic Biol Med 62:65–75
Williams M, Todd GD, Roney N, Crawford J, Coles C, McClure PR, Garey JD, Zaccaria K, Citra M (2012) Toxicological profile for manganese. Atlanta (GA): Agency for Toxic Substances and Disease Registry (US)
Oulhote Y, Mergler D, Bouchard MF (2014) Sex- and age-differences in blood manganese levels in the U.S. general population: national health and nutrition examination survey 2011–2012. Environ Health 13:87
Pine M, Lee B, Dearth R et al (2005) Manganese acts centrally to stimulate luteinizing hormone secretion: a potential influence on female pubertal development. Toxicol Sci 85(2):880–885
Lee B, Pine M, Johnson L et al (2006) Manganese acts centrally to activate reproductive hormone secretion and pubertal development in male rats. Reprod Toxicol 22(4):580–585
Iqbal S, Ali I, Rust P et al (2020) Selenium, zinc, and manganese status in pregnant women and its relation to maternal and child complications. Nutrients 12(3):580
Klotz LO, Kröncke KD, Buchczyk DP et al (2003) Role of copper, zinc, selenium and tellurium in the cellular defense against oxidative and nitrosative stress. J Nutr 133(5 Suppl 1):1448s-s1451
Sun Y, Wang W, Guo Y et al (2019) High copper levels in follicular fluid affect follicle development in polycystic ovary syndrome patients: population-based and in vitro studies. Toxicol Appl Pharmacol 365:101–111
Kurdoglu Z, Kurdoglu M, Demir H et al (2012) Serum trace elements and heavy metals in polycystic ovary syndrome. Hum Exp Toxicol 31(5):452–456
Mariath AB, Bergamaschi DP, Rondó PH et al (2011) The possible role of selenium status in adverse pregnancy outcomes. Br J Nutr 105(10):1418–1428
Bizon A, Tchorz A, Madej P et al (2022) The activity of superoxide dismutase, its relationship with the concentration of zinc and copper and the prevalence of rs2070424 superoxide dismutase gene in women with polycystic ovary syndrome-preliminary study. J Clin Med 11(9):2548
Babaei H, Roshangar L, Sakhaee E et al (2012) Ultrastructural and morphometrical changes of mice ovaries following experimentally induced copper poisoning. Iran Red Crescent Med J 14(9):558–568
Yin J, Hong X, Ma J et al (2020) Serum trace elements in patients with polycystic ovary syndrome: a systematic review and meta-analysis. Front Endocrinol (Lausanne) 11:572384
Schmalbrock LJ, Weiss G, Rijntjes E et al (2021) Pronounced trace element variation in follicular fluids of subfertile women undergoing assisted reproduction. Nutrients 13(11):976
Nasiadek M, Stragierowicz J, Klimczak M et al (2020) The role of zinc in selected female reproductive system disorders. Nutrients 12(8):62
Garner TB, Hester JM, Carothers A et al (2021) Role of zinc in female reproduction. Biol Reprod 104(5):976–994
Maksura H, Akon N, Islam MN et al (2021) Effects of estradiol on in vitro maturation of buffalo and goat oocytes. Reprod Med Biol 20(1):62–70
Barman S, Srinivasan K (2017) Attenuation of oxidative stress and cardioprotective effects of zinc supplementation in experimental diabetic rats. Br J Nutr 117(3):335–350
Piacenza F, Giacconi R, Costarelli L et al (2021) Age, sex, and BMI influence on copper, zinc, and their major serum carrier proteins in a large European population including nonagenarian offspring from MARK-AGE study. J Gerontol A Biol Sci Med Sci 76(12):2097–2106
Yu ZP, Le GW, Shi YH (2005) Effect of zinc sulphate and zinc methionine on growth, plasma growth hormone concentration, growth hormone receptor and insulin-like growth factor-I gene expression in mice. Clin Exp Pharmacol Physiol 32(4):273–278
Bluteau G, Conrozier T, Mathieu P et al (2001) Matrix metalloproteinase-1, -3, -13 and aggrecanase-1 and -2 are differentially expressed in experimental osteoarthritis. Biochim Biophys Acta 1526(2):147–158
Tallant C, Marrero A, Gomis-Rüth FX (2010) Matrix metalloproteinases: fold and function of their catalytic domains. Biochim Biophys Acta 1803(1):20–28
Chakraborty P, Ghosh S, Goswami SK et al (2013) Altered trace mineral milieu might play an aetiological role in the pathogenesis of polycystic ovary syndrome. Biol Trace Elem Res 152(1):9–15
Nazıroğlu M, Dikici DM, Dursun S (2012) Role of oxidative stress and Ca2+ signaling on molecular pathways of neuropathic pain in diabetes: focus on TRP channels. Neurochem Res 37(10):2065–2075
Jang YJ, Ryu HJ, Choi YO et al (2004) Effects of an intracellular Ca(2+) chelator on insulin resistance and hypertension in high-fat-fed rats and spontaneously hypertensive rats. Metabolism 53(3):269–272
Shojaeian Z, Sadeghi R, Latifnejad RR (2019) Calcium and vitamin D supplementation effects on metabolic factors, menstrual cycles and follicular responses in women with polycystic ocvary syndrome: A systematic review and meta-analysis. Caspian J Intern Med 10(4):359–369
Aoki K, Miyagawa K (1990) Correlation of increased serum calcium with elevated blood pressure and vascular resistance during calcium infusion in normotensive man. J Hypertens 8(6):579–583
Morais JBS, Severo JS, De Alencar GRR et al (2017) Effect of magnesium supplementation on insulin resistance in humans: a systematic review. Nutrition 38:54–60
Babapour M, Mohammadi H, Kazemi M et al (2021) Associations between serum magnesium concentrations and polycystic ovary syndrome status: a systematic review and meta-analysis. Biol Trace Elem Res 199(4):1297–1305
Tarleton EK (2018) Factors influencing magnesium consumption among adults in the United States. Nutr Rev 76(7):526–538
Lim SS, Davies MJ, Norman RJ et al (2012) Overweight, obesity and central obesity in women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update 18(6):618–637
Afshar Ebrahimi F, Foroozanfard F, Aghadavod E et al (2018) The effects of magnesium and zinc co-supplementation on biomarkers of inflammation and oxidative stress, and gene expression related to inflammation in polycystic ovary syndrome: a randomized controlled clinical trial. Biol Trace Elem Res 184(2):300–307
Lokman M, Ashraf E, Kassab RB et al (2022) Aluminum chloride-induced reproductive toxicity in rats: the protective role of zinc oxide nanoparticles. Biol Trace Elem Res 200(9):4035–4044
Yokel RA (2020) Aluminum reproductive toxicity: a summary and interpretation of scientific reports. Crit Rev Toxicol 50(7):551–593
Skalny AV, Kopylov PY, Paoliello MMB et al (2021) Hair lead, aluminum, and other toxic metals in normal-weight and obese patients with coronary heart disease. Int J Environ Res Public Health 18(15):nzz108
He FJ, Markandu ND, Sagnella GA et al (2001) Effect of salt intake on renal excretion of water in humans. Hypertension 38(3):317–320
Cornelius F, Habeck M, Kanai R et al (2015) General and specific lipid-protein interactions in Na. K-ATPase Biochim Biophys Acta 1848(9):1729–1743
Hamilton KP, Zelig R, Parker AR et al (2019) Insulin resistance and serum magnesium concentrations among women with polycystic ovary syndrome. Curr Dev Nutr 3(11):nzz108
Kim JW, Kang KM, Yoon TK et al (2014) Study of circulating hepcidin in association with iron excess, metabolic syndrome, and BMP-6 expression in granulosa cells in women with polycystic ovary syndrome. Fertil Steril 102(2):548-554.e2
Marinelli S, Napoletano G, Straccamore M et al (2022) Female obesity and infertility: outcomes and regulatory guidance. Acta Biomed 93(4):e2022278
Aleid A, Alturaifi MY, Alharbi RI, Saleh F, Alomari LH, Hazazi R, Sindi HA, Ahmed RA, Al Mutair A (2023) Assessing the impact of high body mass index (BMI) on the efficacy of assisted reproductive technologies (ART) in Saudi Women: A cross-sectional study examining ovarian reserve and treatment outcomes. Cureus 15(10):e46706
Silvestrim RL, Bos-Mikich A, Kulmann MIR et al (2019) The effects of overweight and obesity on assisted reproduction technology outcomes. JBRA Assist Reprod 23(3):281–286
Jie HY, Zhou X, Zhao MP et al (2022) Pregnancy outcomes in patients with polycystic ovary syndrome who conceived after single thawed blastocyst transfer: a propensity score-matched study. BMC Pregnancy Childbirth 22(1):718
Artini PG, Obino MER, Micelli E et al (2020) Effect of d-chiro-inositol and alpha-lipoic acid combination on COH outcomes in overweight/obese PCOS women. Gynecol Endocrinol 36(9):755–759
Freeland-Graves JH, Sanjeevi N, Lee JJ (2015) Global perspectives on trace element requirements. J Trace Elem Med Biol 31:135–141
Funding
This work was supported by grants Natural Science Foundation of Hunan Province of China (#2021JJ30598, 2021JJ30593, #2020JJ4536) and China Scholarship Council Grant (#CSC201708430228).
Author information
Authors and Affiliations
Contributions
Dan Yin and Rui Mao contributed to the conception of the study and wrote the manuscript; Die Wang, ** Yu and Cuilan Zhou contributed significantly to analysis and manuscript preparation; Jun Liu, Suyun Li, Yulin Nie performed the draws and processed the data of the manuscript; Hongqing Liao, Cuiying Peng helped perform the analysis with constructive discussions.
Corresponding authors
Ethics declarations
Competing Interests
The authors declare no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Attestation Statement.
• The subjects in this trial have not concomitantly been involved in other randomized trials (If applicable).
• Data regarding any of the subjects in the study has not been previously published unless specified.
• Data will be made available to the editors of the journal for review or query upon request.
Capsule: The plasma levels of metal elements might influence the ART outcomes in PCOS patients.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Yin, D., Mao, R., Wang, D. et al. Association of Plasma Metal Levels with Outcomes of Assisted Reproduction in Polycystic Ovary Syndrome. Biol Trace Elem Res (2024). https://doi.org/10.1007/s12011-024-04085-9
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s12011-024-04085-9