Serum 25-hydroxyvitamin D level and risk of benign prostatic hyperplasia: a prospective cohort study of 195,074 males

Background: Benign prostatic hyperplasia (BPH) gives rise to benign prostatic enlargement owing to unregulated hyperplasia of the epithelial and fibromuscular components within the transition zone and periurethral area. Vitamin D is a pleiotropic steroid hormone with functions that encompass the modulation of calcium and phosphate metabolism and the preservation of skeletal health, but prospective evidence in BPH is unclear. Methods: We analyzed data from 195,074 participants in the UK Biobank (recruited 2006–2010) with valid vitamin D measurements and without prevalent BPH. Serum vitamin D was measured using the chemiluminescent immunoassay approach (units: nmol/L). Incident BPH cases were identified through linkage to hospital, primary care, and death registry records until 2022. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Vitamin D was modeled as both a continuous variable and in quartiles. Dose-response relationships were examined using restricted cubic splines, with thresholds determined by maximally selected rank statistics. Subgroup and sensitivity analyses assessed robustness. Results: Over a median follow-up of 13.3 years, 21,168 incident BPH cases were documented. Lower serum vitamin D was associated with an increased risk of BPH. Multivariable-adjusted HRs (95% CIs) were calculated for participants grouped by serum 25-hydroxyvitamin D (25(OH)D) quartiles, yielding values of 1.00 (reference), 0.95 (0.91, 0.99), 0.94 (0.90, 0.98), and 0.95 (0.91, 0.98) for the first to fourth quartiles, respectively. Each 1-standard deviation (SD = 20.9) increase corresponded to a 2% lower risk (HR = 0.98, 95% CI: 0.97–0.99). Restricted cubic spline analysis revealed a progressive decrease in risk with evidence of nonlinearity, which may exist due to saturation effect. Conclusions: Based on large-scale prospective cohort data from the UK Biobank, this study validates that serum 25(OH)D levels are inversely associated with BPH risk.

Benign prostatic hyperplasia; Lower urinary tract symptoms; Vitamin D; 25-hydroxyvitamin D; UK Biobank

[1] Inamura S, Terada N. Chronic inflammation in benign prostatic hyperplasia: pathophysiology and treatment options. International Journal of Urology. 2024; 31: 968–974.

[2] Sandhu JS, Bixler BR, Dahm P, Goueli R, Kirkby E, Stoffel JT, et al. Management of lower urinary tract symptoms attributed to benign prostatic hyperplasia (BPH): AUA guideline amendment 2023. The Journal of Urology. 2024; 211: 11–19.

[3] Ng M, Baradhi KM. Benign prostatic hyperplasia. StatPearls: Treasure Island (FL). 2025.

[4] Lin L, Wang W, Shao Y, Li X, Zhou L. National prevalence and incidence of benign prostatic hyperplasia/lower urinary tract symptoms and validated risk factors pattern. The Aging Male. 2025; 28: 2478875.

[5] Wei JT, Dauw CA, Brodsky CN. Lower urinary tract symptoms in men: a review. JAMA. 2025; 334: 809–821.

[6] Huang J, Chan CK, Yee S, Deng Y, Bai Y, Chan SC, et al. Global burden and temporal trends of lower urinary tract symptoms: a systematic review and meta-analysis. Prostate Cancer and Prostatic Diseases. 2023; 26: 421–428.

[7] Gacci M, Sakalis VI, Karavitakis M, Cornu JN, Gratzke C, Herrmann TRW, et al. European association of urology guidelines on male urinary incontinence. European Urology. 2022; 82: 387–398.

[8] Lin YH, Wu CT, Juang HH. Exploring the complex interplay: BPH, nocturia, and aging male health. World Journal of Urology. 2024; 42: 105.

[9] Li X, Cao X, Zhang J, Fu J, Mohedaner M, Danzengzhuoga, et al. Accelerated aging mediates the associations of unhealthy lifestyles with cardiovascular disease, cancer, and mortality. Journal of the American Geriatrics Society. 2024; 72: 181–193.

[10] Johnson TV, Abbasi A, Ehrlich SS, Kleris RS, Chirumamilla SL, Schoenberg ED, et al. Major depression drives severity of American Urological Association symptom index. Urology. 2010; 76: 1317–1320.

[11] Zhang W, Ding Z, Peng Y, Wang H, Sun Y, Ke H, et al. LUTS/BPH increases the risk of depressive symptoms among elderly adults: a 5-year longitudinal evidence from CHARLS. Journal of Affective Disorders. 2024; 367: 210–218.

[12] van Exel NJ, Koopmanschap MA, McDonnell J, Chapple CR, Berges R, Rutten FF. Medical consumption and costs during a one-year follow-up of patients with LUTS suggestive of BPH in six European countries: report of the TRIUMPH study. European Urology. 2006; 49: 92–102.

[13] Becker J, Moch H. Pathology and pathophysiology of BPH and relevant incidental findings in TUR-P. Therapeutische Umschau. 2023; 80: 147–157. (In German)

[14] Fu X, Wang Y, Lu Y, Liu J, Li H. Association between metabolic syndrome and benign prostatic hyperplasia: the underlying molecular connection. Life Sciences. 2024; 358: 123192.

[15] Gadhvi J, Goueli R, Roehrborn C, Strand D. Improving patient selection for BPH medical and surgical therapy through a deeper understanding of prostate cellular and molecular biology. The Urologic Clinics of North America. 2025; 52: 503–508.

[16] Ramasamy I. Vitamin D metabolism and guidelines for vitamin D supplementation. The Clinical Biochemist Reviews. 2020; 41: 103–126.

[17] Delrue C, Speeckaert MM. Vitamin D and vitamin D-binding protein in health and disease. International Journal of Molecular Sciences. 2023; 24: 4642.

[18] Wimalawansa SJ. Physiology of vitamin D-focusing on disease prevention. Nutrients. 2024; 16: 1666.

[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. The Journal of Clinical Endocrinology and Metabolism. 2011; 96: 1911–1930.

[20] Midttun M, Overgaard K, Zerahn B, Pedersen M, Rashid A, Østergren PB, et al. Beneficial effects of exercise, testosterone, vitamin D, calcium and protein in older men—a randomized clinical trial. Journal of Cachexia, Sarcopenia and Muscle. 2024; 15: 1451–1462.

[21] Zhang Q, Zhang Z, He X, Liu Z, Shen L, Long C, et al. Vitamin D levels and the risk of overactive bladder: a systematic review and meta-analysis. Nutrition Reviews. 2024; 82: 166–175.

[22] Boot IWA, Wesselius A, Yu EYW, White E, Brustad M, Marques C, et al. Dietary vitamin D intake and the bladder cancer risk: a pooled analysis of prospective cohort studies. Clinical Nutrition. 2023; 42: 1462–1474.

[23] Hussain S, Yates C, Campbell MJ. Vitamin D and systems biology. Nutrients. 2022; 14: 5197.

[24] Trump DL, Deeb KK, Johnson CS. Vitamin D: considerations in the continued development as an agent for cancer prevention and therapy. Cancer Journal. 2010; 16: 1–9.

[25] Krishnan AV, Feldman D. Mechanisms of the anti-cancer and anti-inflammatory actions of vitamin D. Annual Review of Pharmacology and Toxicology. 2011; 51: 311–336.

[26] Yoo S, Oh S, Kim HS, Choi HS, Park J, Cho SY, et al. Impact of serum 25-OH vitamin D level on lower urinary tract symptoms in men: a step towards reducing overactive bladder. BJU International. 2018; 122: 667–672.

[27] Autier P, Boniol M, Pizot C, Mullie P. Vitamin D status and ill health: a systematic review. The Lancet Diabetes & Endocrinology. 2014; 2: 76–89.

[28] Park SG, Yeo JK, Cho DY, Park MG. Impact of metabolic status on the association of serum vitamin D with hypogonadism and lower urinary tract symptoms/benign prostatic hyperplasia. The Aging Male. 2018; 21: 55–59.

[29] Sudlow C, Gallacher J, Allen N, Beral V, Burton P, Danesh J, et al. UK Biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLOS Medicine. 2015; 12: e1001779.

[30] Schwartz GG, Whitlatch LW, Chen TC, Lokeshwar BL, Holick MF. Human prostate cells synthesize 1,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3. Cancer Epidemiology, Biomarkers & Prevention. 1998; 7: 391–395.

[31] Krishnan AV, Feldman D. Molecular pathways mediating the anti-inflammatory effects of calcitriol: implications for prostate cancer chemoprevention and treatment. Endocrine-Related Cancer. 2010; 17: R19–R38.

[32] Chauss D, Freiwald T, McGregor R, Yan B, Wang L, Nova-Lamperti E, et al. Autocrine vitamin D signaling switches off pro-inflammatory programs of TH1 cells. Nature Immunology. 2022; 23: 62–74.

[33] Blutt SE, Allegretto EA, Pike JW, Weigel NL. 1,25-dihydroxyvitamin D3 and 9-cis-retinoic acid act synergistically to inhibit the growth of LNCaP prostate cells and cause accumulation of cells in G1. Endocrinology. 1997; 138: 1491–1497.

[34] Krishnan AV, Shinghal R, Raghavachari N, Brooks JD, Peehl DM, Feldman D. Analysis of vitamin D-regulated gene expression in LNCaP human prostate cancer cells using cDNA microarrays. Prostate. 2004; 59: 243–251.

[35] Espinosa G, Esposito R, Kazzazi A, Djavan B. Vitamin D and benign prostatic hyperplasia—a review. The Canadian Journal of Urology. 2013; 20: 6820–6825.

[36] Nickel JC, Roehrborn CG, O’Leary MP, Bostwick DG, Somerville MC, Rittmaster RS. The relationship between prostate inflammation and lower urinary tract symptoms: examination of baseline data from the REDUCE trial. European Urology. 2008; 54: 1379–1384.

[37] Chen Y, Zhang J, Ge X, Du J, Deb DK, Li YC. Vitamin D receptor inhibits nuclear factor κB activation by interacting with IκB kinase β protein. The Journal of Biological Chemistry. 2013; 288: 19450–19458.

[38] Baek EB, Eun HS, Song JY, Hong EJ, Park SH, Kumbukgahadeniya P, et al. Vitamin D supplementation ameliorates ductular reaction, liver inflammation and fibrosis in mice by upregulating TXNIP in ductular cells. Nature Communications. 2025; 16: 4420.

[39] Shany S, Sigal-Batikoff I, Lamprecht S. Vitamin D and myofibroblasts in fibrosis and cancer: at cross-purposes with TGF-β/SMAD signaling. Anticancer Research. 2016; 36: 6225–6234.

[40] Wimalawansa SJ. Vitamin D deficiency: effects on oxidative stress, epigenetics, gene regulation, and aging. Biology. 2019; 8: 30.

[41] Moslemi E, Musazadeh V, Kavyani Z, Naghsh N, Shoura SMS, Dehghan P. Efficacy of vitamin D supplementation as an adjunct therapy for improving inflammatory and oxidative stress biomarkers: an umbrella meta-analysis. Pharmacological Research. 2022; 186: 106484.

[42] Moyad MA. Vitamin D and the vital need for more VITALs: seeking causation amidst escalating association, inflammation, and supplementation. The Journal of Urology. 2023; 209: 29–31.

[43] Trump DL, Aragon-Ching JB. Vitamin D in prostate cancer. Asian Journal of Andrology. 2018; 20: 244–252.

[44] Xu G, Dai G, Huang Z, Guan Q, Du C, Xu X. The etiology and pathogenesis of benign prostatic hyperplasia: the roles of sex hormones and anatomy. Research and Reports in Urology. 2024; 16: 205–214.

[45] Murphy AB, Nyame YA, Batai K, Kalu R, Khan A, Gogana P, et al. Does prostate volume correlate with vitamin D deficiency among men undergoing prostate biopsy? Prostate Cancer and Prostatic Diseases. 2017; 20: 55–60.

[46] Yousefi T, Yousef Memar M, Ahmadi Jazi A, Zand S, Reiter RJ, Amirkhanlou S, et al. Molecular pathways and biological roles of melatonin and vitamin D; effects on immune system and oxidative stress. International Immunopharmacology. 2024; 143: 113548.

[47] Ruan L. Association between vitamin D receptor gene polymorphisms and genetic susceptibility to benign prostatic hyperplasia: a systematic review and meta-analysis. Medicine. 2024; 103: e37361.

[48] Maggi M, Crescioli C, Morelli A, Colli E, Adorini L. Pre-clinical evidence and clinical translation of benign prostatic hyperplasia treatment by the vitamin D receptor agonist BXL-628 (Elocalcitol). Journal of Endocrinological Investigation. 2006; 29: 665–674.

[49] Burgess S, Butterworth A, Malarstig A, Thompson SG. Use of Mendelian randomisation to assess potential benefit of clinical intervention. The BMJ. 2012; 345: e7325.

[50] Lucas JA, Bolland MJ, Grey AB, Ames RW, Mason BH, Horne AM, et al. Determinants of vitamin D status in older women living in a subtropical climate. Osteoporosis International. 2005; 16: 1641–1648.