Causal relationship between serum mineral and vitamin levels and male infertility: a two-sample Mendelian randomization study_West China Medical Journal

Authors：

SONG Wenzhu ^1,2 , LIANG Xiaoling ³ , SONG Wenhao ⁴ ,  LI Yaheng ^1,2,5

1. Department of Nephrology, Shanxi Provincial People’s Hospital, Taiyuan, Shanxi 030001, P. R. China;
2. Department of Nephrology, Fifth Clinical Medical College of Shanxi Medical University (Shanxi Provincial People’s Hospital), Shanxi Provincial Key Laboratory of Nephrology, Taiyuan, Shanxi 030001, P. R. China;
3. Jiedongyi Community Health Service Station, Xiaolan Town, Zhongshan, Guangdong 528414, P. R. China;
4. Dongsheng Hospital, Zhongshan, Guangdong 528414, P. R. China;
5. Department of Laboratory, Heping Campus, Shanxi Provincial People’s Hospital, Taiyuan, Shanxi 030012, P. R. China;

Corresponding?author：

LI Yaheng, Email: yueliyou@126.com

Keywords：

Micronutrients; male infertility; causal effect; risk factors; Mendelian randomization

DOI：

10.7507/1002-0179.202412036

Video：

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Objective To employ Mendelian randomization (MR) to assess the potential causal relationship between 15 micronutrients in serum and male infertility, so as to provide a scientific basis for the etiological prevention of male infertility. Methods Male infertility was taken as the outcome variable, and 15 serum micronutrients was regarded as the potential influencing factors. A two-sample MR analysis was conducted using genome-wide association study with the European population. Multivariable MR analysis was employed to explore the independent effects of potential micronutrients on male infertility. Results A total of 198 single nucleotide polymorphisms across 15 groups were included as instrumental variables to assess the causal association between micronutrients and male infertility. Univariate analysis showed that increased serum iron levels were positively causally associated with a higher risk of male infertility (odds ratio=2.917, P=0.015). Besides, multivariate MR analysis suggested that this positive causal relationship between iron and male infertility remains significant (odds ratio=3.253, P=0.029). Meanwhile, this study found a negative association between elevated vitamin D levels and the risk of male infertility (odds ratio=0.403, P=0.020).Conclusion Elevated serum iron levels and increased vitamin D levels are associated with significant positive and negative causal effects on male infertility, respectively.

Citation： SONG Wenzhu, LIANG Xiaoling, SONG Wenhao, LI Yaheng. Causal relationship between serum mineral and vitamin levels and male infertility: a two-sample Mendelian randomization study. West China Medical Journal, 2025, 40(12): 1988-1992. doi: 10.7507/1002-0179.202412036 Copy

1.	中國醫師協會生殖醫學專業委員會生殖男科學組男性不育癥的內分泌治療中國專家共識編寫組. 男性不育癥的內分泌治療中國專家共識. 中華生殖與避孕雜志, 2023, 43(3): 235-245.
2.	Eisenberg ML, Esteves SC, Lamb DJ, et al. Male infertility. Nat Rev Dis Primers, 2023, 9(1): 49.
3.	Chen T, Belladelli F, Del Giudice F, et al. Male fertility as a marker for health. Reprod Biomed Online, 2022, 44(1): 131-144.
4.	李恪丞, 孫龍吉, 孫松, 等. 男性不育與前列腺癌發病風險相關的孟德爾隨機化分析. 中國性科學, 2024, 33(7): 26-30.
5.	廖書杰, 徐巖英, 孫瑞娟, 等. 中國"男性生殖健康"基礎研究在國家自然科學基金支持下的 30 年發展概況. 中華男科學雜志, 2020, 26(1): 3-16.
6.	周植星, 陳美靈, 張曉東, 等. 男性生殖系統用藥生殖毒性評價的監管要求和關注要點. 中國臨床藥理學雜志, 2023, 39(21): 3183-3192.
7.	李校敏, 陳志聰, 安庚. 高能量飲食及肥胖影響男性生育力的研究進展. 中國科學: 生命科學, 2024, 54(1): 103-115.
8.	Basic M, Mitic D, Krstic M, et al. Tobacco and alcohol as factors for male infertility-a public health approach. J Public Health (Oxf), 2023, 45(2): e241-e249.
9.	宋文柱, 宋文浩, 梁小玲, 等. 血清微量營養素與高血壓因果關聯的孟德爾隨機化研究. 現代預防醫學, 2024, 51(21): 3867-3872.
10.	陳甫, 劉斌, 和帥軍, 等. 男性不育患者精液質量與精漿微量元素水平及精漿外泌體 miR-184 水平的關系. 實用醫學雜志, 2024, 40(7): 930-935.
11.	吳添天. 血清微量元素及激素水平檢測對男性不育的診斷分析. 醫學理論與實踐, 2021, 34(5): 853-855.
12.	劉浩, 張敏. 精漿中微量元素與男性不育的關系探討. 中國計劃生育學雜志, 2020, 28(7): 1098-1100.
13.	Karabulut S, Korkmaz S, Güne? E, et al. Seminal trace elements and their relationship with sperm parameters. Andrologia, 2022, 54(11): e14610.
14.	Shen S, Gao X, Song X, et al. Association between inflammatory bowel disease and rosacea: a bidirectional two-sample Mendelian randomization study. J Am Acad Dermatol, 2024, 90(2): 401-403.
15.	Feng X, Zhang L, Hou Y, et al. Mendelian randomization analysis reveals causal factors behind Alzheimer's disease risk: evidence, opportunities, and challenges. J Prev Alzheimers Dis, 2024, 11(3): 749-758.
16.	黃素蘭, 葛良清, 歐陽文. 基于雙樣本孟德爾隨機化分析探討血尿酸水平與子癇前期的因果關聯. 中國優生與遺傳雜志, 2025, 33(3): 506-512.
17.	申猛, 張新中. 血清微量元素和未破裂顱內動脈瘤形成因果關聯的孟德爾隨機化研究. 巴楚醫學, 2025, 8(3): 88-94.
18.	Zheng J, Baird D, Borges MC, et al. Recent developments in Mendelian randomization studies. Curr Epidemiol Rep, 2017, 4(4): 330-345.
19.	Yuan S, Larsson SC. Coffee and caffeine consumption and risk of kidney stones: a Mendelian randomization study. Am J Kidney Dis, 2022, 79(1): 9-14. e1.
20.	Gao RC, Sang N, Jia CZ, et al. Association between sleep traits and rheumatoid arthritis: a Mendelian randomization study. Front Public Health, 2022, 10: 940161.
21.	Bowden J, Davey Smith G, Haycock PC, et al. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol, 2016, 40(4): 304-314.
22.	Chen L, Zhao R, Zhang Y. Association between adjustable dietary factors and periodontitis: NHANES 2009-2014 and Mendelian randomization. J Transl Med, 2025, 23(1): 353.
23.	Tsao CW, Liao YR, Chang TC, et al. Effects of iron supplementation on testicular function and spermatogenesis of iron-deficient rats. Nutrients, 2022, 14(10): 2063.
24.	張琴, 蘇占營, 吳成亮. 嚴重少弱精子癥患者血液和精液中微量元素含量分析及相關性研究. 現代醫藥衛生, 2023, 39(20): 3459-3462.
25.	Zheng Z, Liu L, Zhou K, et al. Anti-oxidant and anti-endothelial dysfunctional properties of nano-selenium in vitro and in vivo of hyperhomocysteinemic rats. Int J Nanomedicine, 2020, 15: 4501-4521.
26.	He WB, Tu CF, Liu Q, et al. DMC1 mutation that causes human non-obstructive azoospermia and premature ovarian insufficiency identified by whole-exome sequencing. J Med Genet, 2018, 55(3): 198-204.
27.	Vo HVT, Nguyen YT, Kim N, et al. Vitamin A, D, E, and K as matrix metalloproteinase-2/9 regulators that affect expression and enzymatic activity. Int J Mol Sci, 2023, 24(23): 17038.
28.	DeLuca HF. Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr, 2004, 80(6 Suppl): 1689s-1696s.
29.	Yuan C, Xiang L, Jian Z, et al. Vitamin D levels and risk of male factor infertility: a Mendelian randomization Study. World J Mens Health, 2023, 41(3): 640-648.
30.	Jueraitetibaike K, Ding Z, Wang DD, et al. The effect of vitamin D on sperm motility and the underlying mechanism. Asian J Androl, 2019, 21(4): 400-407.
31.	Lee GY, Han SN. The role of Vitamin E in immunity. Nutrients, 2018, 10(11): 1614.
32.	Dawson EB, Harris WA, Powell LC. Relationship between ascorbic acid and male fertility. World Rev Nutr Diet, 1990, 62: 1-26.
33.	de Ligny W, Smits RM, Mackenzie-Proctor R, et al. Antioxidants for male subfertility. Cochrane Database Syst Rev, 2022, 5(5): Cd007411.
34.	Zareba P, Colaci DS, Afeiche M, et al. Semen quality in relation to antioxidant intake in a healthy male population. Fertil Steril, 2013, 100(6): 1572-1579.
35.	Ko EY, Sabanegh ES Jr. The role of over-the-counter supplements for the treatment of male infertility--fact or fiction?. J Androl, 2012, 33(3): 292-308.
36.	Kacem O, Harzallah M, Zedini C, et al. Beneficial effect of an oral antioxidant supplementation (fertimax2) on IVF-ICSI outcomes: a preliminary clinical study. Adv Databases Inf Syst, 2014, 2(3): 47-56.

1. 中國醫師協會生殖醫學專業委員會生殖男科學組男性不育癥的內分泌治療中國專家共識編寫組. 男性不育癥的內分泌治療中國專家共識. 中華生殖與避孕雜志, 2023, 43(3): 235-245.
2. Eisenberg ML, Esteves SC, Lamb DJ, et al. Male infertility. Nat Rev Dis Primers, 2023, 9(1): 49.
3. Chen T, Belladelli F, Del Giudice F, et al. Male fertility as a marker for health. Reprod Biomed Online, 2022, 44(1): 131-144.
4. 李恪丞, 孫龍吉, 孫松, 等. 男性不育與前列腺癌發病風險相關的孟德爾隨機化分析. 中國性科學, 2024, 33(7): 26-30.
5. 廖書杰, 徐巖英, 孫瑞娟, 等. 中國"男性生殖健康"基礎研究在國家自然科學基金支持下的 30 年發展概況. 中華男科學雜志, 2020, 26(1): 3-16.
6. 周植星, 陳美靈, 張曉東, 等. 男性生殖系統用藥生殖毒性評價的監管要求和關注要點. 中國臨床藥理學雜志, 2023, 39(21): 3183-3192.
7. 李校敏, 陳志聰, 安庚. 高能量飲食及肥胖影響男性生育力的研究進展. 中國科學: 生命科學, 2024, 54(1): 103-115.
8. Basic M, Mitic D, Krstic M, et al. Tobacco and alcohol as factors for male infertility-a public health approach. J Public Health (Oxf), 2023, 45(2): e241-e249.
9. 宋文柱, 宋文浩, 梁小玲, 等. 血清微量營養素與高血壓因果關聯的孟德爾隨機化研究. 現代預防醫學, 2024, 51(21): 3867-3872.
10. 陳甫, 劉斌, 和帥軍, 等. 男性不育患者精液質量與精漿微量元素水平及精漿外泌體 miR-184 水平的關系. 實用醫學雜志, 2024, 40(7): 930-935.
11. 吳添天. 血清微量元素及激素水平檢測對男性不育的診斷分析. 醫學理論與實踐, 2021, 34(5): 853-855.
12. 劉浩, 張敏. 精漿中微量元素與男性不育的關系探討. 中國計劃生育學雜志, 2020, 28(7): 1098-1100.
13. Karabulut S, Korkmaz S, Güne? E, et al. Seminal trace elements and their relationship with sperm parameters. Andrologia, 2022, 54(11): e14610.
14. Shen S, Gao X, Song X, et al. Association between inflammatory bowel disease and rosacea: a bidirectional two-sample Mendelian randomization study. J Am Acad Dermatol, 2024, 90(2): 401-403.
15. Feng X, Zhang L, Hou Y, et al. Mendelian randomization analysis reveals causal factors behind Alzheimer's disease risk: evidence, opportunities, and challenges. J Prev Alzheimers Dis, 2024, 11(3): 749-758.
16. 黃素蘭, 葛良清, 歐陽文. 基于雙樣本孟德爾隨機化分析探討血尿酸水平與子癇前期的因果關聯. 中國優生與遺傳雜志, 2025, 33(3): 506-512.
17. 申猛, 張新中. 血清微量元素和未破裂顱內動脈瘤形成因果關聯的孟德爾隨機化研究. 巴楚醫學, 2025, 8(3): 88-94.
18. Zheng J, Baird D, Borges MC, et al. Recent developments in Mendelian randomization studies. Curr Epidemiol Rep, 2017, 4(4): 330-345.
19. Yuan S, Larsson SC. Coffee and caffeine consumption and risk of kidney stones: a Mendelian randomization study. Am J Kidney Dis, 2022, 79(1): 9-14. e1.
20. Gao RC, Sang N, Jia CZ, et al. Association between sleep traits and rheumatoid arthritis: a Mendelian randomization study. Front Public Health, 2022, 10: 940161.
21. Bowden J, Davey Smith G, Haycock PC, et al. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol, 2016, 40(4): 304-314.
22. Chen L, Zhao R, Zhang Y. Association between adjustable dietary factors and periodontitis: NHANES 2009-2014 and Mendelian randomization. J Transl Med, 2025, 23(1): 353.
23. Tsao CW, Liao YR, Chang TC, et al. Effects of iron supplementation on testicular function and spermatogenesis of iron-deficient rats. Nutrients, 2022, 14(10): 2063.
24. 張琴, 蘇占營, 吳成亮. 嚴重少弱精子癥患者血液和精液中微量元素含量分析及相關性研究. 現代醫藥衛生, 2023, 39(20): 3459-3462.
25. Zheng Z, Liu L, Zhou K, et al. Anti-oxidant and anti-endothelial dysfunctional properties of nano-selenium in vitro and in vivo of hyperhomocysteinemic rats. Int J Nanomedicine, 2020, 15: 4501-4521.
26. He WB, Tu CF, Liu Q, et al. DMC1 mutation that causes human non-obstructive azoospermia and premature ovarian insufficiency identified by whole-exome sequencing. J Med Genet, 2018, 55(3): 198-204.
27. Vo HVT, Nguyen YT, Kim N, et al. Vitamin A, D, E, and K as matrix metalloproteinase-2/9 regulators that affect expression and enzymatic activity. Int J Mol Sci, 2023, 24(23): 17038.
28. DeLuca HF. Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr, 2004, 80(6 Suppl): 1689s-1696s.
29. Yuan C, Xiang L, Jian Z, et al. Vitamin D levels and risk of male factor infertility: a Mendelian randomization Study. World J Mens Health, 2023, 41(3): 640-648.
30. Jueraitetibaike K, Ding Z, Wang DD, et al. The effect of vitamin D on sperm motility and the underlying mechanism. Asian J Androl, 2019, 21(4): 400-407.
31. Lee GY, Han SN. The role of Vitamin E in immunity. Nutrients, 2018, 10(11): 1614.
32. Dawson EB, Harris WA, Powell LC. Relationship between ascorbic acid and male fertility. World Rev Nutr Diet, 1990, 62: 1-26.
33. de Ligny W, Smits RM, Mackenzie-Proctor R, et al. Antioxidants for male subfertility. Cochrane Database Syst Rev, 2022, 5(5): Cd007411.
34. Zareba P, Colaci DS, Afeiche M, et al. Semen quality in relation to antioxidant intake in a healthy male population. Fertil Steril, 2013, 100(6): 1572-1579.
35. Ko EY, Sabanegh ES Jr. The role of over-the-counter supplements for the treatment of male infertility--fact or fiction?. J Androl, 2012, 33(3): 292-308.
36. Kacem O, Harzallah M, Zedini C, et al. Beneficial effect of an oral antioxidant supplementation (fertimax2) on IVF-ICSI outcomes: a preliminary clinical study. Adv Databases Inf Syst, 2014, 2(3): 47-56.

West China Medical Journal

Causal relationship between serum mineral and vitamin levels and male infertility: a two-sample Mendelian randomization study

Abstract Full text Figures/Tables Video References Cited by

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