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Effects of vitamin D and L-cysteine cosupplementation on circulating bioavailable and total 25-hydroxy-vitamin D, the free/total testosterone ratio and inflammatory biomarkers in healthy vitamin D-deficient African Americans: A placebo-controlled double-blind clinical trial

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Jain, Sushil K, Justin Margret, Jeffrey, Zachary, Alonzo, Lally, Marissa M, Vanchiere, John A, Mhanna, Maroun J, Shi, Runhua, Levine, Steven N·2024·BMJ Nutrition, Prevention & Health
DOI 10.1136/bmjnph-2023-000856PMC PMC11773665
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Abstract

Background: Subjects with metabolic syndrome and obesity have higher levels of inflammation with depression of the vitamin D (VD) hydroxylase/metabolising genes ( CYP2R1/CYP27A1/CYP27B1/VDR ) required to convert VD consumed in the diet into 25(OH)VD. Compared with total 25(OH)VD levels, measurement of bioavailable 25(OH)VD is a better method to determine the beneficial effect of VD. Objective: This study investigates whether cosupplementation with VD and L-cysteine (LC), which downregulates inflammation and upregulates VD-regulating genes, provides a better therapeutic benefit than supplementation with VD-alone in African Americans (AA). Methods: AA participants (men/women, aged 18–65 years; n=165) were block randomised into one of four groups and received daily, oral supplementation for 6 months with placebo, LC (1000 mg/day), VD (2000 IU/day) or VD+LC. Fasting blood collected at the baseline and final visits was analysed for total, free and bioavailable 25(OH)VD along with insulin, VD-binding protein (VDBP), sex hormone-binding globulin (SHBG), free and total testosterone, and inflammatory marker levels. Studies were carried out in THP-1 monocytes to elucidate the direct effect of LC and testosterone on VD-regulating genes. Results: Baseline data showed no differences in age, body mass index, calcium, liver or kidney function among the groups. Compared with levels in the group that received VD-alone supplementation, levels of neutrophil-to-lymphocyte ratio, C reactive protein, HOMA-IR, VDBP and HbA1c were significantly lower in the VD+LC group while the VD+LC group showed a significant increase in bioavailable 25(OH)VD in both sexes, total 25(OH)VD levels were significantly elevated in men but not in women treated with VD+LC. Blood levels of SHBG and free/total testosterone were elevated in the VD+LC group but not in the VD-alone group. LC and testosterone treatment significantly upregulated VD-metabolising genes ( CYP2R1/CYP27A1/CYP27B1/VDR ) and SHBG in THP-1 monocytes. Conclusions: VD cosupplemented with LC upregulates circulating bioavailable 25(OH)VD and reduces inflammation. Total 25(OH)VD levels were higher in men but not in women in the VD+LC group. This pilot study suggests that compared with supplementation with VD-alone, VD+LC cosupplementation could be a better approach to raising the total 25(OH)VD in men and the bioavailable 25(OH)VD in both sexes and lowering the inflammatory risk in the AA population. Trial registration number: NCT04939792 .

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  • Existing trials have yielded mixed findings: some reported increases in total testosterone, calculated free testosterone, bioactive testosterone, or free androgen index after supplementation, whereas others showed no meaningful change in total testosterone, SHBG, or free testosterone-related outcomes.

    “Existing trials have yielded mixed findings: some reported increases in TT, calculated FT, BAT, or FAI after supplementation, whereas others showed no meaningful change in TT, SHBG, or FT-related outcomes [17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33].”

    From Vitamin D Supplementation, Total Testosterone, and Androgen Bioavailability Markers in Adult Men: A Systematic Review and Meta-Analysis of Randomized Controlled Trials (2026) · cites this paper as [26]

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Research works printed but not linked: 39

  1. [1]Holick MF The vitamin D deficiency pandemic: approaches for diagnosis, treatment and prevention Rev Endocr Metab Disord 2017 18 153 65 10.1007/s11154-017-9424-1 28516265 · DOI
  2. [2]Shapses SA Calvo MS Health benefits of vitamin D supplementation: time to move the spotlight away from bone health in vitamin D-replete individuals Am J Clin Nutr 2023 118 489 90 10.1016/j.ajcnut.2023.06.017 37661100 · DOI
  3. [3]Vearing RM Hart KH Darling AL et al Global perspective of the vitamin D status of African-Caribbean populations: a systematic review and meta-analysis Eur J Clin Nutr 2022 76 516 26 10.1038/s41430-021-00980-9 34282293 PMC8993683 · DOI
  4. [4]Maretzke F Bechthold A Egert S et al Role of vitamin D in preventing and treating selected Extraskeletal diseases-an umbrella review Nutrients 2020 12 969 10.3390/nu12040969 32244496 PMC7231149 · DOI
  5. [5]Bouillon R Manousaki D Rosen C et al The health effects of vitamin D supplementation: evidence from human studies Nat Rev Endocrinol 2022 18 96 110 10.1038/s41574-021-00593-z 34815552 PMC8609267 · DOI · Paper page
  6. [6]Boucher BJ Why do so many trials of vitamin D supplementation fail Endocr Connect 2020 9 R195 206 10.1530/EC-20-0274 33052876 PMC7487184 · DOI
  7. [7]Lin KW Vitamin D screening and supplementation in primary care: time to curb our enthusiasm Am Fam Physician 2018 97 226 7 29671531
  8. [8]Jain SK Kanikarla-Marie P Warden C et al L-Cysteine supplementation upregulates glutathione (GSH) and vitamin D binding protein (VDBP) in hepatocytes cultured in high glucose and in vivo in liver, and increases blood levels of GSH, VDBP, and 25-hydroxy-vitamin D in Zucker diabetic fatty rats Mol Nutr Food Res 2016 60 1090 8 10.1002/mnfr.201500667 26778482 PMC4876732 · DOI
  9. [9]Jain SK Parsanathan R Achari AE et al Glutathione stimulates vitamin D regulatory and glucose-metabolism genes, LOWERS oxidative stress and inflammation, and increases 25-hydroxy-vitamin D levels in blood: a novel approach to treat 25-Hydroxyvitamin D deficiency Antioxid Redox Signal 2018 29 1792 807 10.1089/ars.2017.7462 30160165 PMC6208166 · DOI
  10. [10]Elkhwanky M-S Kummu O Piltonen TT et al Obesity represses CYP2R1, the vitamin D 25-hydroxylase, in the liver and extrahepatic tissues JBMR Plus 2020 4 e10397 10.1002/jbm4.10397 33210060 PMC7657391 · DOI · Paper page
  11. [11]Roizen JD Long C Casella A et al Obesity decreases hepatic 25-hydroxylase activity causing low serum 25-Hydroxyvitamin D J Bone Miner Res 2019 34 1068 73 10.1002/jbmr.3686 30790351 PMC6663580 · DOI
  12. [12]Mokhtari V Afsharian P Shahhoseini M et al A review on various uses of N-acetyl Cysteine Cell J 2017 19 11 7 10.22074/cellj.2016.4872 28367412 PMC5241507 · DOI
  13. [13]Clemente Plaza N Reig García-Galbis M Martínez-Espinosa RM Effects of the usage of L-Cysteine (L-Cys) on human health Molecules 2018 23 575 10.3390/molecules23030575 29510494 PMC6017824 · DOI
  14. [14]Bikle DD The free hormone hypothesis: when, Why, and how to measure the free hormone levels to assess vitamin D, thyroid, sex hormone, and cortisol status JBMR Plus 2021 5 e10418 10.1002/jbm4.10418 33553985 PMC7839820 · DOI · Paper page
  15. [15]Bikle DD Malmstroem S Schwartz J Current controversies: are free vitamin metabolite levels a more accurate assessment of vitamin D status than total levels Endocrinol Metab Clin North Am 2017 46 901 18 10.1016/j.ecl.2017.07.013 29080642 PMC5675107 · DOI
  16. [16]Fang A-P Long J-A Zhang Y-J et al Serum bioavailable, rather than total, 25-Hydroxyvitamin D levels are associated with hepatocellular carcinoma survival Hepatology 2020 72 169 82 10.1002/hep.31013 31677282 PMC7496975 · DOI
  17. [17]Zhu A Kuznia S Boakye D et al Vitamin D-binding protein, bioavailable, and free 25(OH)D, and mortality: a systematic review and meta-analysis Nutrients 2022 14 3894 10.3390/nu14193894 36235547 PMC9571577 · DOI
  18. [18]Ginde AA Liu MC Camargo CA Demographic differences and trends of vitamin D insufficiency in the US population, 1988-2004 Arch Intern Med 2009 169 626 32 10.1001/archinternmed.2008.604 19307527 PMC3447083 · DOI · Paper page
  19. [19]Sterling RK Lissen E Clumeck N et al Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection Hepatology 2006 43 1317 25 10.1002/hep.21178 16729309 · DOI · Paper page
  20. [20]Jain SK Micinski D Parsanathan R L-Cysteine stimulates the effect of vitamin D on inhibition of oxidative stress, IL-8, and MCP-1 secretion in high glucose treated monocytes J Am Coll Nutr 2021 40 327 32 10.1080/07315724.2020.1850371 33596158 · DOI
  21. [21]Kanikarla-Marie P Jain SK L-Cysteine supplementation reduces high-glucose and ketone-induced adhesion of monocytes to endothelial cells by inhibiting ROS Mol Cell Biochem 2014 391 251 6 10.1007/s11010-014-2009-3 24627243 · DOI
  22. [22]Parsanathan R Achari AE Manna P et al L-Cysteine and vitamin D Co-supplementation alleviates markers of musculoskeletal disorders in vitamin D-deficient high-fat diet-Fed mice Nutrients 2020 12 3406 10.3390/nu12113406 33171932 PMC7694620 · DOI
  23. [23]Justin Margret J Jain SK Overview of gene expression techniques with an emphasis on vitamin D related studies Curr Med Res Opin 2023 39 205 17 10.1080/03007995.2022.2159148 36537177 · DOI
  24. [24]Zhu A Kuznia S Niedermaier T et al Vitamin D-binding protein, total, "Nonbioavailable," bioavailable, and free 25-Hydroxyvitamin D, and mortality in a large population-based cohort of older adults J Intern Med 2022 292 463 76 10.1111/joim.13494 35373871 · DOI
  25. [25]Safarinejad MR Safarinejad S Efficacy of selenium and/or N-acetyl-Cysteine for improving semen parameters in infertile men: a double-blind, placebo controlled, randomized study J Urol 2009 181 741 51 10.1016/j.juro.2008.10.015 19091331 · DOI
  26. [26]Jannatifar R Parivar K Roodbari NH et al Effects of N-acetyl-Cysteine supplementation on sperm quality, chromatin integrity and level of oxidative stress in infertile men Reprod Biol Endocrinol 2019 17 24 10.1186/s12958-019-0468-9 30771790 PMC6377938 · DOI
  27. [27]Song M Graubard BI Rabkin CS et al Neutrophil-to-lymphocyte ratio and mortality in the United States general population Sci Rep 2021 11 464 10.1038/s41598-020-79431-7 33431958 PMC7801737 · DOI · Paper page
  28. [28]Liu C-C Ko H-J Liu W-S et al Neutrophil-to-lymphocyte ratio as a predictive marker of metabolic syndrome Medicine (Baltimore) 2019 98 e17537 10.1097/MD.0000000000017537 31651856 PMC6824790 · DOI
  29. [29]Duncan A Talwar D McMillan DC et al Quantitative data on the magnitude of the systemic inflammatory response and its effect on micronutrient status based on plasma measurements Am J Clin Nutr 2012 95 64 71 10.3945/ajcn.111.023812 22158726 · DOI
  30. [31]Li H Pham T McWhinney BC et al Sex hormone binding globulin modifies testosterone action and metabolism in prostate cancer cells Int J Endocrinol 2016 2016 6437585 10.1155/2016/6437585 27990161 PMC5136390 · DOI · Paper page
  31. [32]Laurent MR Hammond GL Blokland M et al Sex hormone-binding globulin regulation of androgen Bioactivity in vivo: validation of the free hormone hypothesis Sci Rep 2016 6 35539 10.1038/srep35539 27748448 PMC5066276 · DOI · Paper page
  32. [33]Simó R Sáez-López C Barbosa-Desongles A et al Novel insights in SHBG regulation and clinical implications Trends Endocrinol Metab 2015 26 376 83 10.1016/j.tem.2015.05.001 26044465 · DOI · Paper page
  33. [34]Saez-Lopez C Villena JA Simó R et al Sex hormone-binding globulin overexpression protects against high-fat diet-induced obesity in transgenic male mice J Nutr Biochem 2020 85 108480 10.1016/j.jnutbio.2020.108480 32795655 · DOI · Paper page
  34. [35]Bourebaba N Ngo T Śmieszek A et al Sex hormone binding globulin as a potential drug candidate for liver-related metabolic disorders treatment Biomed Pharmacother 2022 153 113261 10.1016/j.biopha.2022.113261 35738176 · DOI
  35. [36]Turkes GF Uysal S Demir T et al Associations between bioavailable vitamin D and remnant cholesterol in patients with type 2 diabetes mellitus Cureus 2021 13 e13248 10.7759/cureus.13248 33728195 PMC7948319 · DOI
  36. [37]Foresta C Strapazzon G De Toni L et al Bone mineral density and testicular failure: evidence for a role of vitamin D 25-hydroxylase in human Testis J Clin Endocrinol Metab 2011 96 E646 52 10.1210/jc.2010-1628 21270327 · DOI
  37. [38]Hu Y Wang L Yang G et al VDR promotes testosterone synthesis in Mouse Leydig cells via regulation of cholesterol side chain cleavage cytochrome P450 (Cyp11A1) expression Genes Genomics 2023 45 1377 87 10.1007/s13258-023-01444-z 37747642 · DOI
  38. [39]Yeap BB Almeida OP Hyde Z et al Higher serum free testosterone is associated with better cognitive function in older men, while total testosterone is not Clin Endocrinol (Oxf) 2008 68 404 12 10.1111/j.1365-2265.2007.03055.x 17888021 · DOI · Paper page
  39. [40]Kravchick S Peled R Dorfman D et al Predictive criteria for prostate cancer detection in men with serum PSA concentration of 2.0 to 4.0 ng/mL Urology 2005 66 542 6 10.1016/j.urology.2005.04.012 16140074 · DOI

Cited by

Sorted by citations

Authors
Jain, S. K., Justin Margret, J., Zachary, A., Lally, M. M., Vanchiere, J. A., Mhanna, M. J., Shi, R., & Levine, S. N.
Affiliations
  • Louisiana State University Health Sciences Center Shreveport (US)
  • Department of Pediatrics, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA
Corresponding author
Jain, Sushil K
ORCID
Venue
BMJ Nutrition, Prevention & Health
Publisher
BMJ
Published
2024-07-02
Volume
7
Issue
2
Pages
230-239
ISSN
2516-5542 (ISSN-L)
DOI
10.1136/bmjnph-2023-000856
PMC
PMC11773665
OpenAlex
W4400232598
Cited by
4
References
1
Citations by year
2026: 2 · 2024: 2
FWCI
1.13
Type
journal article
Language
en
Open access
Licence
Locations
  • BMJ Nutrition Prevention & Health (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
NIH/NCCIH (3R33 AT010637-02S1, 5R33AT010637)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Vitamin D Research Studies
  • Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutrition and Health Studies
Keywords
vitamin D supplementation, cysteine, 25-hydroxyvitamin D, bioavailable vitamin D, free testosterone, sex hormone-binding globulin, inflammatory markers, C-reactive protein, neutrophil-to-lymphocyte ratio, insulin resistance, vitamin D binding protein, CYP27B1, CYP2R1, CYP27A1, vitamin D receptor, THP-1 cells

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