Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Nonlinear association between vitamin D levels and response to tadalafil 5 mg daily treatment in erectile dysfunction patients: a prospective cohort study

International Journal of Impotence Research (2026)Cite this article

Subjects

Abstract

Erectile dysfunction (ED) is a common male sexual disorder. Vitamin D (VD) deficiency is frequent in ED patients and has been associated with greater disease severity, but its role in predicting treatment response remains unclear. In this prospective cohort study, 202 ED patients were initially enrolled, and after excluding 30 ineligible cases, 172 were included in the final analysis at Chengdu University of TCM Affiliated Hospital (September 2023–August 2024). ED severity was evaluated using the International Index of Erectile Function-5 (IIEF-5) during a 1-month follow-up, with 152 patients (88.4%) reporting symptomatic improvement after daily tadalafil 5 mg treatment. Patients with VD ≥ 20 ng/mL showed faster responses. Multivariate Cox regression demonstrated a significant positive association between baseline VD levels and treatment outcomes (adjusted hazard ratio = 1.60 per 1 ng/mL increase; 95% confidence interval: 1.31–1.95). Restricted Cubic Spline analysis revealed a nonlinear relationship, with the strongest effect observed at VD ≤ 19.6 ng/mL, representing a data-driven inflection point. Interaction analyses further confirmed consistent benefits across all age groups. These findings indicate that baseline VD is an independent prognostic factor for tadalafil efficacy in ED, highlighting its potential clinical utility for risk stratification and individualized treatment decisions in ED.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Flowchart.
Fig. 2: Comparison of Model Indices.
Fig. 3: Restricted Cubic Spline.
Fig. 4: Interacted Restricted Cubic Spline (VD with Age).

Similar content being viewed by others

Data availability

The dataset generated during the current study was available from the corresponding author on reasonable request.

References

  1. Zhang X, Yang B, Li N, Li H. Prevalence and risk factors for erectile dysfunction in chinese adult males. J Sex Med. 2017;14:1201–8. https://doi.org/10.1016/j.jsxm.2017.08.009.

    Article  PubMed  Google Scholar 

  2. NIH Consensus Conference. Impotence. NIH consensus development panel on impotence. JAMA. 1993;270:83–90. https://doi.org/10.1001/jama.1993.03510010089036.

    Article  Google Scholar 

  3. McCabe MP, Sharlip ID, Lewis R, Atalla E, Balon R, Fisher AD, et al. Incidence and prevalence of sexual dysfunction in women and men: a consensus statement from the fourth international consultation on sexual medicine 2015. J Sex Med. 2016;13:144–52. https://doi.org/10.1016/j.jsxm.2015.12.034.

    Article  PubMed  Google Scholar 

  4. Ayta IA, McKinlay JB, Krane RJ. The likely worldwide increase in erectile Dysfunction between 1995 and 2025 and some possible policy consequences. BJU Int. 1999;84:50–56. https://doi.org/10.1046/j.1464-410x.1999.00142.x.

    Article  PubMed  CAS  Google Scholar 

  5. Sheng Z. Psychological consequences of erectile dysfunction. Trends Urol Mens Health. 2021;12:19–22. https://doi.org/10.1002/tre.827.

    Article  Google Scholar 

  6. Delrue C, Speeckaert MM. Vitamin D and Vitamin D-binding protein in health and disease. Int J Mol Sci. 2023;24:4642 https://doi.org/10.3390/ijms24054642.

    Article  PubMed  PubMed Central  Google Scholar 

  7. DeLuca HF. Vitamin D endocrinology. Ann Intern Med. 1976;85:367–77. https://doi.org/10.7326/0003-4819-85-3-367.

    Article  PubMed  CAS  Google Scholar 

  8. Farag YMK, Guallar E, Zhao D, Kalyani RR, Blaha MJ, Feldman DI, et al. Vitamin D deficiency is independently associated with greater prevalence of erectile dysfunction: the national health and nutrition examination survey (NHANES) 2001-4. Atherosclerosis. 2016;252:61–67. https://doi.org/10.1016/j.atherosclerosis.2016.07.921.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Horsanalı MO, Eren H, Dil E, Caglayan A, Erdogan O, Ekren F. Novel predictive risk factor of erectile dysfunction: Serum 25‐hydroxy vitamin D. Andrologia. 2020;52:e13767 https://doi.org/10.1111/and.13767.

    Article  PubMed  CAS  Google Scholar 

  10. Crafa A, Cannarella R, Condorelli RA, La Vignera S, Calogero AE. Is there an association between vitamin D deficiency and erectile dysfunction? a systematic review and meta-analysis. Nutrients. 2020;12:1411 https://doi.org/10.3390/nu12051411.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Duarte Romero B, Waterhouse M, Baxter C, McLeod DSA, English DR, Armstrong BK, et al. The effect of three years of vitamin D supplementation on erectile dysfunction: results from the randomized placebo-controlled D-Health Trial. Clin Nutr ESPEN. 2024;60:109–15. https://doi.org/10.1016/j.clnesp.2024.01.011.

    Article  PubMed  Google Scholar 

  12. Elshahid AR, Zaky AM, Goda YMH, Ismail NF. Relationship between vitamin D receptors gene polymorphism and arteriogenic erectile dysfunction. Urologia. 2024;91:592–7. https://doi.org/10.1177/03915603241241430.

    Article  PubMed  Google Scholar 

  13. Crafa A, Cannarella R, Barbagallo F, Leanza C, Palazzolo R, Flores HA, et al. Mechanisms suggesting a relationship between vitamin D and erectile dysfunction: an overview. Biomolecules. 2023;13:930 https://doi.org/10.3390/biom13060930.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Wang R, Zheng T, Zhang TB, Li R, Wang ZL, Yang F, et al. Efficacy and safety of sildenafil citrate in treatment of erectile dysfunction. Natl J Androl. 2019;25:603–7. https://doi.org/10.13263/j.cnki.nja.2019.07.005. Article in Chinese].

    Article  Google Scholar 

  15. Rosen RC, Cappelleri JC, Smith MD, Lipsky J, Peña BM. Development and evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction. Int J Impot Res. 1999;11:319–26. https://doi.org/10.1038/sj.ijir.3900472.

    Article  PubMed  CAS  Google Scholar 

  16. Chinese Urological Association. Diagnosis and treatment guidelines for erectile dysfunction. Chin J Androl. 2022;28:722–55. https://doi.org/10.13263/j.cnki.nja.2022.08.009. Article in Chinese].

    Article  Google Scholar 

  17. Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999;84:3666–72. https://doi.org/10.1210/jcem.84.10.6079.

    Article  PubMed  CAS  Google Scholar 

  18. Rosen RC, Allen KR, Ni X, Araujo AB. Minimal clinically important differences in the erectile function domain of the international index of erectile function scale. Eur Urol. 2011;60:1010–6. https://doi.org/10.1016/j.eururo.2011.07.053.

    Article  PubMed  Google Scholar 

  19. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96:1911–30. https://doi.org/10.1210/jc.2011-0385.

    Article  PubMed  CAS  Google Scholar 

  20. Portest S. A primer on model selection using the akaike information criterion. Infect Dis Model. 2020;5:111–28. https://doi.org/10.1016/j.idm.2019.12.010.

    Article  Google Scholar 

  21. Marrie RA, Dawson NV, Garland A. Quantile regression and restricted cubic splines are useful for exploring relationships between continuous variables. J Clin Epidemiol. 2009;62:511–.e1. https://doi.org/10.1016/j.jclinepi.2008.05.015.

    Article  PubMed  Google Scholar 

  22. MacDonald SM, Burnett AL. Physiology of erection and pathophysiology of erectile dysfunction. Urol Clin North Am. 2021;48:513–25. https://doi.org/10.1016/j.ucl.2021.06.009.

    Article  PubMed  Google Scholar 

  23. Toda N, Ayajiki K, Okamura T. Nitric oxide and penile erectile function. Pharmacol Ther. 2005;106:233–66. https://doi.org/10.1016/j.pharmthera.2004.11.011.

    Article  PubMed  CAS  Google Scholar 

  24. Andrukhova O, Slavic S, Zeitz U, Riesen SC, Heppelmann MS, Ambrisko TD, et al. Vitamin D is a regulator of endothelial nitric oxide synthase and arterial stiffness in mice. Mol Endocrinol. 2014;28:53–64. https://doi.org/10.1210/me.2013-1252.

    Article  PubMed  CAS  Google Scholar 

  25. Molinari C, Uberti F, Grossini E, Vacca G, Carda S, Invernizzi M, et al. 1α,25-Dihydroxycholecalciferol induces nitric oxide production in cultured endothelial cells. Cell Physiol Biochem. 2011;27:661–8. https://doi.org/10.1159/000330075.

    Article  PubMed  CAS  Google Scholar 

  26. Lin CS, Lin G, Xin ZC, Lue TF. Expression, distribution and regulation of phosphodiesterase 5. Curr Pharm Des. 2006;12:3439–57. https://doi.org/10.2174/138161206778343064.

    Article  PubMed  CAS  Google Scholar 

  27. Grossman E. The role of tadalafil in treated hypertensive patients with erectile dysfunction. J Clin Hypertens. 2022;24:182–3. https://doi.org/10.1111/jch.14434.

    Article  Google Scholar 

  28. Taskiran M, Dogan K. The efficacy of systemic inflammatory response and oxidative stress in erectile dysfunction through multi-inflammatory index: a prospective cross-sectional analysis. J Sex Med. 2023;20:591–6. https://doi.org/10.1093/jsxmed/qdad037.

    Article  PubMed  Google Scholar 

  29. Querfeld U. Vitamin D and inflammation. Pediatr Nephrol. 2013;28:605–10. https://doi.org/10.1007/s00467-012-2377-4.

    Article  PubMed  Google Scholar 

  30. De Vita F, Lauretani F, Bauer J, Bautmans I, Shardell M, Cherubini A, et al. Relationship between vitamin D and inflammatory markers in older individuals. Age. 2014;36:9694 https://doi.org/10.1007/s11357-014-9694-4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Defeudis G, Mazzilli R, Tenuta M, Rossini G, Zamponi V, Olana S, et al. Erectile dysfunction and diabetes: A melting pot of circumstances and treatments. Diabetes Metab Res Rev. 2021;38:e3494 https://doi.org/10.1002/dmrr.3494.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Ma WJ, Qin M, Cui TW, Zhang XP, Ke ZH, Pan ZK, et al. Relationship between the risk factors of cardiovascular disease by testing biochemical markers and young men with erectile dysfunction: a case-control study. Transl Androl Urol. 2021;10:724 https://doi.org/10.21037/tau-20-1056.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Fujita N, Okamoto T, Yamamoto H, Yoneyama T, Hashimoto Y, Mikami T, et al. Association between sex hormones and erectile dysfunction in men without hypoandrogenism. Sci Rep. 2024;14:13433 https://doi.org/10.1038/s41598-024-64339-3.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Park CY, Shin S, Han SN. Multifaceted roles of vitamin D for diabetes: from immunomodulatory functions to metabolic regulations. Nutrients. 2024;16:3185 https://doi.org/10.3390/nu16183185.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Radkhah N, Zarezadeh M, Jamilian P, Ostadrahimi A. The effect of vitamin D supplementation on lipid profiles: an umbrella review of meta-analyses. Adv Nutr. 2023;14:1479–98. https://doi.org/10.1016/j.advnut.2023.08.012.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Wang XX, Jiang T, Shen Y, Santamaria H, Solis N, Arbeeny C, et al. Vitamin D receptor agonist doxercalciferol modulates dietary fat-induced renal disease and renal lipid metabolism. Am J Physiol Renal Physiol. 2011;300:F801 https://doi.org/10.1152/ajprenal.00338.2010.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Hofer D, Münzker J, Schwetz V, Ulbing M, Hutz K, Stiegler P, et al. Testicular synthesis and vitamin D action. J Clin Endocrinol Metab. 2014;99:3766–73. https://doi.org/10.1210/jc.2014-1690.

    Article  PubMed  CAS  Google Scholar 

  38. Wehr E, Pilz S, Boehm BO, März W, Obermayer-Pietsch B. Association of vitamin D status with serum androgen levels in men. Clin Endocrinol (Oxf). 2010;73:243–8. https://doi.org/10.1111/j.1365-2265.2009.03777.x.

    Article  PubMed  CAS  Google Scholar 

  39. Pilz S, Frisch S, Koertke H, Kuhn J, Dreier J, Obermayer-Pietsch B, et al. Effect of vitamin D supplementation on testosterone levels in men. Horm Metab Res. 2010;43:223–5. https://doi.org/10.1055/s-0030-1269854.

    Article  PubMed  CAS  Google Scholar 

  40. Burnett AL, Nehra A, Breau RH, Culkin DJ, Faraday MM, Hakim LS, et al. Erectile dysfunction: AUA guideline. J Urol. 2018;200:633–41. https://doi.org/10.1016/j.juro.2018.05.004.

    Article  PubMed  Google Scholar 

  41. Zhou A, Selvanayagam JB, Hyppönen E. Non-linear Mendelian randomization analyses support a role for vitamin D deficiency in cardiovascular disease risk. Eur Heart J. 2022;43:1731–9. https://doi.org/10.1093/eurheartj/ehab809.

    Article  PubMed  CAS  Google Scholar 

  42. Zhang JJ, Yu HC, Geng TT, Zhang JJ, Zhou XT, Wang YX, et al. Serum 25-hydroxyvitamin D concentrations, vitamin D receptor polymorphisms, and risk of infections among individuals with type 2 diabetes: a prospective cohort study. Am J Clin Nutr. 2024;120:398–406. https://doi.org/10.1016/j.ajcnut.2024.06.007.

    Article  PubMed  CAS  Google Scholar 

  43. Sofianopoulou E, Kaptoge SK, Afzal S, Jiang T, Gill D, Gundersen TE, et al. Estimating dose-response relationships for vitamin D with coronary heart disease, stroke, and all-cause mortality: observational and Mendelian randomisation analyses. Lancet Diabetes Endocrinol. 2024;12:e2–e11. https://doi.org/10.1016/S2213-8587(23)00287-5.

    Article  Google Scholar 

  44. Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the institute of medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011;96:53–58. https://doi.org/10.1210/jc.2010-2704.

    Article  PubMed  CAS  Google Scholar 

  45. Kupelian V, Link CL, Rosen RC, McKinlay JB. Socioeconomic status, not race/ethnicity, contributes to variation in the prevalence of erectile dysfunction: results from the boston area community health (BACH) Survey. J Sex Med. 2008;5:1325–33. https://doi.org/10.1111/j.1743-6109.2008.00822.x.

    Article  PubMed  Google Scholar 

  46. Irfan M, Hussain NHN, Noor NM, Mohamed M, Sidi H, Ismail SB. Epidemiology of male sexual dysfunction in asian and european regions: a systematic review. Am J Mens Health. 2020;14:1557988320937200 https://doi.org/10.1177/1557988320937200.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Cai Z, Li H. Developing a prediction model for the self-evaluation of erectile dysfunction in an adult male population. Andrologia. 2021;53:e13880 https://doi.org/10.1111/and.13880.

    Article  PubMed  Google Scholar 

  48. Zhao LM, Jiang H, Hong K, Liu DF, Ma LL, Zhu JC. Analysis of the benefits of tadalafil for patients with erectile dysfunction. Chin J Androl. 2011;17:89–92. https://doi.org/10.13263/j.cnki.nja.2011.01.021. Article in Chinese].

    Article  Google Scholar 

  49. Jiang H, Zhao LM, Yan S, Liu JH, Zhu ZH, Luo JD, et al. Long-term tadalafil once daily in Chinese men with erectile dysfunction: a 2-year final analysis of a post-marketing, multicenter, randomized, open-label trial. Asian J Androl. 2024;26:282–7. https://doi.org/10.4103/aja202370.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Wang CM, Wu BR, Xiang P, Xiao J, Hu XC. Management of male erectile dysfunction: From the past to the future. Front Endocrinol (Lausanne). 2023;14:1148834 https://doi.org/10.3389/fendo.2023.1148834.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Salonia, Capogrosso A, Boeri P, Cocci L, Corona G A, Dinkelman-Smit M, et al. European association of urology guidelines on male sexual and reproductive health: 2025 update on male hypogonadism, erectile dysfunction, premature ejaculation, and peyronie’s disease. Eur Urol. 2025;S0302-2838:00211–8. https://doi.org/10.1016/j.eururo.2025.04.010.

    Article  Google Scholar 

Download references

Acknowledgements

The authors extend their sincere gratitude to all individuals and organizations that have contributed to the successful completion of this study. Our deepest appreciation goes to the patients who participated in this research, acknowledging their patience and support throughout the study. We express our thanks to the staff at the Affiliated Hospital of Chengdu University of Traditional Chinese Medicine for their invaluable assistance in patient recruitment and data collection. We are also grateful to our colleagues in the Urology and Andrology departments of the same hospital for their insightful discussions and technical support throughout the course of this study. Special acknowledgment is due to our supervisor, Professor Cai Jian, for his significant contributions to the research ideas, data analysis, and manuscript preparation. His guidance was instrumental in shaping this work. Lastly, we extend our sincere thanks to the anonymous reviewers for their constructive feedback, which substantially enhanced the quality of our manuscript.

Funding

No funding was obtained for this study.

Author information

Author notes

  1. These authors contributed equally: Hang Yang, Hao Tan.

Authors and Affiliations

  1. Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China

    Hang Yang, Hao Tan & Qing Li

  2. Department of Urology and Andrology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China

    Juan Zhao & Jian Cai

Authors
  1. Hang Yang
    View author publications

    Search author on:PubMed Google Scholar

  2. Hao Tan
    View author publications

    Search author on:PubMed Google Scholar

  3. Juan Zhao
    View author publications

    Search author on:PubMed Google Scholar

  4. Qing Li
    View author publications

    Search author on:PubMed Google Scholar

  5. Jian Cai
    View author publications

    Search author on:PubMed Google Scholar

Contributions

Hang Yang: Methodology, Data collection, Analysis, Writing – original draft. Hao Tan: Data collection, Writing - Review & Editing. Juan Zhao: Data collection, Writing - Review & Editing. Qing Li: Data collection, Writing & Editing. Jian Cai: Methodology, Data collection, Writing - Review & Editing.

Corresponding author

Correspondence to Jian Cai.

Ethics declarations

Ethical Evaluation

The treatment methods used in our study are in accordance with clinical standards. All data collection was conducted with the informed consent of the patients. We did not collect any sensitive personal information, and all data were anonymized. After consulting with the local ethical review board, it was determined that our study does not require an ethical review. This decision was based on the minimal risk posed to participants and the absence of sensitive or personal data that could compromise their privacy.

Competing interests

The present study is an independent and original work, with no competing interests or conflicts with any organization or related publications.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

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.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, H., Tan, H., Zhao, J. et al. Nonlinear association between vitamin D levels and response to tadalafil 5 mg daily treatment in erectile dysfunction patients: a prospective cohort study. Int J Impot Res (2026). https://doi.org/10.1038/s41443-026-01242-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • DOI: https://doi.org/10.1038/s41443-026-01242-7

Search

Advanced search

Quick links