Skip to main content

Advertisement

SpringerLink
Log in

Genetically elevated bioavailable testosterone level was associated with the occurrence of benign prostatic hyperplasia

  • Original Article
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Background

Recent studies identified several risk factors of benign prostatic hyperplasia (BPH), including dyslipidemia, type 2 diabetes mellitus, hypertension, and obesity. But they were not so reliable and some studies contradicted with one another. Hence, a reliable method is urgently needed to explore exact factors that facilitated BPH development.

Methods

The study was based on Mendelian randomization (MR) design. All participants were from the most recent genome-wide association studies (GWAS) with large sample size. The causal associations between nine phenotypes (total testosterone level, bioavailable testosterone level, sex hormone-binding globulin, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, type 2 diabetes mellitus, hyper-tension, and body mass index) and BPH outcome were estimated. Two sample MR, bidirectional MR, and multivariate MR (MVMR) were performed.

Results

Increase in bioavailable testosterone level was able to induce BPH based on nearly all combination methods [beta (95% confidence interval (CI)): 0.20 (0.06–0.34) for inverse variance weighted (IVW)]. The other traits seemed to interact with testosterone level and did not cause BPH generally. Higher triglycerides level was likely to raise bioavailable testosterone level [beta (95% CI): 0.04 (0.01–0.06) for IVW]. In MVMR model, bioavailable testosterone level was still associated with BPH occurrence [beta (95% CI) 0.27 (0.03–0.50) for IVW].

Conclusions

We for the first time validated the central role of bioavailable testosterone level in the pathogenesis of BPH. The complex associations between other traits and BPH should be further investigated.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.

References

  1. Yoo S, Oh S, Suh J, Park J, Cho MC, Jeong H, Won S, Son H (2020) Optimal high-density lipoprotein cholesterol level for decreasing benign prostatic hyperplasia in men not taking statin medication: a historical cohort study. Prostate 80(7):570–576

    Article  CAS  PubMed  Google Scholar 

  2. Shih HJ, Tsai PS, Wen YC, Kao MC, Fan YC, Huang CJ (2020) Hyperlipidemia patients with long-term statin treatment are associated with a reduced risk of progression of benign prostatic enlargement. Aging Male 23(5):354–361

    Article  PubMed  Google Scholar 

  3. Besiroglu H, Dursun M, Otunctemur A, Ozbek E (2017) The association between triglyceride high density lipoprotein cholesterol ratio and benign prostate hyperplasia in non-diabetic patients:a cross-sectional study. Aging Male 20(3):198–204

    CAS  PubMed  Google Scholar 

  4. Feng T, Howard LE, Vidal AC, Moreira DM, Castro-Santamaria R, Andriole GL, Freedland SJ (2017) Serum cholesterol and risk of lower urinary tract symptoms progression: results from the reduction by dutasteride of prostate cancer events study. Int J Urol 24(2):151–156

    Article  CAS  PubMed  Google Scholar 

  5. Gacci M, Corona G, Vignozzi L, Salvi M, Serni S, De Nunzio C, Tubaro A, Oelke M, Carini M, Maggi M (2015) Metabolic syndrome and benign prostatic enlargement: a systematic review and meta-analysis. BJU Int 115(1):24–31

    Article  PubMed  Google Scholar 

  6. Yang X, Zhang Q, Jiang G, Liu J, Xie C, Cui S, Wu T (2019) The effects of statins on benign prostatic hyperplasia and the lower urinary tract symptoms: a Meta-analysis. Medicine (Baltimore) 98(18):e15502

    Article  CAS  PubMed  Google Scholar 

  7. Ornaghi PI, Porreca A, Sandri M, Sciarra A, Falsaperla M, Ludovico GM, Cerruto MA, Antonelli A (2022) Features of patients referring to the outpatient office due to benign prostatic hyperplasia: analysis of a national prospective cohort of 5815 cases. Prostate Cancer Prostatic Dis. Accessed 22 Jul 2022

  8. Chughtai B, Forde JC, Thomas DD, Laor L, Hossack T, Woo HH, Te AE, Kaplan SA (2016) Benign prostatic hyperplasia. Nat Rev Dis Primers 5(2):16031

    Article  Google Scholar 

  9. Vignozzi L, Gacci M, Maggi M (2016) Lower urinary tract symptoms, benign prostatic hyperplasia and metabolic syndrome. Nat Rev Urol 13(2):108–119

    Article  CAS  PubMed  Google Scholar 

  10. Lotti F, Frizza F, Balercia G, Barbonetti A, Behre HM, Calogero AE, Cremers JF, Francavilla F, Isidori AM, Kliesch S, La Vignera S, Lenzi A, Marcou M, Pilatz A, Poolamets O, Punab M, Godoy MFP, Quintian C, Rajmil O, Salvio G, Shaeer O, Weidner W, Maseroli E, Cipriani S, Baldi E, Degl’Innocenti S, Danza G, Caldini AL, Terreni A, Boni L, Krausz C, Maggi M (2022) The European Academy of Andrology (EAA) ultrasound study on healthy, fertile men: Prostate-vesicular transrectal ultrasound reference ranges and associations with clinical, seminal and biochemical characteristics. Andrology 10(6):1150–1171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lotti F, Rastrelli G, Maseroli E, Cipriani S, Guaraldi F, Krausz C, Reisman Y, Sforza A, Maggi M, Corona G (2019) Impact of metabolically healthy obesity in patients with andrological problems. J Sex Med 16(6):821–832

    Article  PubMed  Google Scholar 

  12. Lotti F, Corona G, Vignozzi L, Rossi M, Maseroli E, Cipriani S, Gacci M, Forti G, Maggi M (2014) Metabolic syndrome and prostate abnormalities in male subjects of infertile couples. Asian J Androl 16(2):295–304

    Article  PubMed  PubMed Central  Google Scholar 

  13. Lotti F, Corona G, Colpi GM, Filimberti E, Degli Innocenti S, Mancini M, Baldi E, Noci I, Forti G, Adorini L, Maggi M (2011) Elevated body mass index correlates with higher seminal plasma interleukin 8 levels and ultrasonographic abnormalities of the prostate in men attending an andrology clinic for infertility. J Endocrinol Invest 34(10):e336–e342

    CAS  PubMed  Google Scholar 

  14. Meigs JB, Mohr B, Barry MJ, Collins MM, McKinlay JB (2001) Risk factors for clinical benign prostatic hyperplasia in a community-based population of healthy aging men. J Clin Epidemiol 54(9):935–944

    Article  CAS  PubMed  Google Scholar 

  15. Chiu YL, Kao S, Lin HC, Liu SP, Huang CY (2015) Benign prostatic enlargement is not associated with diabetes: a population-based study. Andrology 3(5):933–936

    Article  CAS  PubMed  Google Scholar 

  16. Elsworth B, Lyon M, Alexander T, Liu Y, Matthews P, Hallett J, Bates P, Palmer T, Haberland V, Smith GD, Zheng J (2020) The MRC IEU openGWAS data infrastructure. https://doi.org/10.1101/2020.08.10.244293

  17. Hemani G, Zheng J, Elsworth B, Wade KH, Haberland V, Baird D, Laurin C, Burgess S, Bowden J, Langdon R, Tan VY, Yarmolinsky J, Shihab HA, Timpson NJ, Evans DM, Relton C, Martin RM, Davey Smith G, Gaunt TR, Haycock PC (2018) The MR-Base platform supports systematic causal inference across the human phenome. Elife 30(7):e34408

    Article  Google Scholar 

  18. Bowden J, Del Greco MF, Minelli C, Davey Smith G, Sheehan NA, Thompson JR (2016) Assessing the suitability of summary data for two-sample Mendelian randomization analyses using MR-Egger regression: the role of the I2 statistic. Int J Epidemiol 45(6):1961–1974

    PubMed  PubMed Central  Google Scholar 

  19. Xiong Y, Zhang Y, Li X, Qin F, Yuan J (2020) The prevalence and associated factors of lower urinary tract symptoms suggestive of benign prostatic hyperplasia in aging males. Aging Male 23(5):1432–1439

    Article  PubMed  Google Scholar 

  20. Xiong Y, Zhang F, Wu C, Zhang Y, Huang X, Qin F, Yuan J (2021) The circadian syndrome predicts lower urinary tract symptoms suggestive of benign prostatic hyperplasia better than metabolic syndrome in aging males: A 4-year follow-up study. Front Med (Lausanne) 21(8):715830

    Article  Google Scholar 

  21. Roehrborn CG (2008) Pathology of benign prostatic hyperplasia. Int J Impot Res 20(Suppl 3):S11–S18

    Article  PubMed  Google Scholar 

  22. Foster CS (2000) Pathology of benign prostatic hyperplasia. Prostate Suppl 9:4–14

    Article  CAS  PubMed  Google Scholar 

  23. Griffiths K, Morton MS, Nicholson RI (1997) Androgens, androgen receptors, antiandrogens and the treatment of prostate cancer. Eur Urol 32(Suppl 3):24–40

    CAS  PubMed  Google Scholar 

  24. Carson C 3rd, Rittmaster R (2003) The role of dihydrotestosterone in benign prostatic hyperplasia. Urology 61(4 Suppl 1):2–7

    Article  PubMed  Google Scholar 

  25. Isaacs JT (1984) Antagonistic effect of androgen on prostatic cell death. Prostate 5(5):545–557

    Article  CAS  PubMed  Google Scholar 

  26. Marberger M, Roehrborn CG, Marks LS, Wilson T, Rittmaster RS (2006) Relationship among serum testosterone, sexual function, and response to treatment in men receiving dutasteride for benign prostatic hyperplasia. J Clin Endocrinol Metab 91(4):1323–1328

    Article  CAS  PubMed  Google Scholar 

  27. Corona G, Vignozzi L, Rastrelli G, Lotti F, Cipriani S, Maggi M (2014) Benign prostatic hyperplasia: a new metabolic disease of the aging male and its correlation with sexual dysfunctions. Int J Endocrinol 2014:329456

    Article  PubMed  PubMed Central  Google Scholar 

  28. Vignozzi L, Gacci M, Cellai I, Santi R, Corona G, Morelli A, Rastrelli G, Comeglio P, Sebastanelli A, Maneschi E, Nesi G, De Nunzio C, Tubaro A, Mannucci E, Carini M, Maggi M (2013) Fat boosts, while androgen receptor activation counteracts. BPH-Assoc Prostate Inflammat Prostate 73(8):789–800

    CAS  Google Scholar 

  29. Vignozzi L, Rastrelli G, Corona G, Gacci M, Forti G, Maggi M (2014) Benign prostatic hyperplasia: a new metabolic disease? J Endocrinol Invest 37(4):313–322

    Article  CAS  PubMed  Google Scholar 

  30. Vignozzi L, Cellai I, Santi R, Lombardelli L, Morelli A, Comeglio P, Filippi S, Logiodice F, Carini M, Nesi G, Gacci M, Piccinni MP, Adorini L, Maggi M (2012) Antiinflammatory effect of androgen receptor activation in human benign prostatic hyperplasia cells. J Endocrinol 214(1):31–43

    Article  CAS  PubMed  Google Scholar 

  31. Pearl JA, Berhanu D, François N, Masson P, Zargaroff S, Cashy J, McVary KT (2013) Testosterone supplementation does not worsen lower urinary tract symptoms. J Urol 190(5):1828–1833

    Article  CAS  PubMed  Google Scholar 

  32. Francomano D, Ilacqua A, Bruzziches R, Lenzi A, Aversa A (2014) Effects of 5-year treatment with testosterone undecanoate on lower urinary tract symptoms in obese men with hypogonadism and metabolic syndrome. Urology 83(1):167–173

    Article  PubMed  Google Scholar 

  33. Ko YH, du Moon G, Moon KH (2013) Testosterone replacement alone for testosterone deficiency syndrome improves moderate lower urinary tract symptoms: one year follow-up. World J Mens Health 31(1):47–52

    Article  PubMed  PubMed Central  Google Scholar 

  34. Shigehara K, Sugimoto K, Konaka H, Iijima M, Fukushima M, Maeda Y, Mizokami A, Koh E, Origasa H, Iwamoto T, Namiki M (2011) Androgen replacement therapy contributes to improving lower urinary tract symptoms in patients with hypogonadism and benign prostate hypertrophy: a randomised controlled study. Aging Male 14(1):53–58

    Article  PubMed  Google Scholar 

  35. Haider A, Gooren LJ, Padungtod P, Saad F (2009) Concurrent improvement of the metabolic syndrome and lower urinary tract symptoms upon normalisation of plasma testosterone levels in hypogonadal elderly men. Andrologia 41(1):7–13

    Article  CAS  PubMed  Google Scholar 

  36. Kalinchenko S, Vishnevskiy EL, Koval AN, Mskhalaya GJ, Saad F (2008) Beneficial effects of testosterone administration on symptoms of the lower urinary tract in men with late-onset hypogonadism: a pilot study. Aging Male 11(2):57–61

    Article  CAS  PubMed  Google Scholar 

  37. Karazindiyanoğlu S, Cayan S (2008) The effect of testosterone therapy on lower urinary tract symptoms/bladder and sexual functions in men with symptomatic late-onset hypogonadism. Aging Male 11(3):146–149

    Article  PubMed  Google Scholar 

  38. Seftel AD, Kathrins M, Niederberger C (2015) Critical update of the 2010 endocrine society clinical practice guidelines for male hypogonadism: a systematic analysis. Mayo Clin Proc 90(8):1104–1115

    Article  PubMed  Google Scholar 

  39. Dean JD, McMahon CG, Guay AT, Morgentaler A, Althof SE, Becher EF, Bivalacqua TJ, Burnett AL, Buvat J, El Meliegy A, Hellstrom WJ, Jannini EA, Maggi M, McCullough A, Torres LO, Zitzmann M (2015) The international society for sexual medicine’s process of care for the assessment and management of testosterone deficiency in adult men. J Sex Med 12(8):1660–1686

    Article  CAS  PubMed  Google Scholar 

  40. Yang G, Schooling CM (2023) Investigating sex-specific associations of lipid traits with type 2 diabetes, glycemic traits and sex hormones using Mendelian randomization. Cardiovasc Diabetol 22(1):3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Vignozzi L, Morelli A, Sarchielli E, Comeglio P, Filippi S, Cellai I, Maneschi E, Serni S, Gacci M, Carini M, Piccinni MP, Saad F, Adorini L, Vannelli GB, Maggi M (2012) Testosterone protects from metabolic syndrome-associated prostate inflammation: an experimental study in rabbit. J Endocrinol 212(1):71–84

    Article  CAS  PubMed  Google Scholar 

  42. Penna G, Fibbi B, Maggi M, Adorini L (2009) Prostate autoimmunity: from experimental models to clinical counterparts. Expert Rev Clin Immunol 5(5):577–586

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We express our thanks to those people who have contributed to the IEU GWAS database project and the MRC Integrative Epidemiology Unit (IEU) at the University of Bristol. Sincere thanks also go to the many GWAS consortia who have made the GWAS data that they generated publicly available, and many members of the IEU who have contributed to curating these data.

Funding

Not applicable.

Author information

Author notes

  1. L. Lin, W. Wang and K. Xiao have contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China

    L. Lin, W. Wang, K. Xiao & L. Zhou

  2. Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, Sichuan, China

    L. Lin, W. Wang, K. Xiao & L. Zhou

  3. Department of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan, China

    X. Guo

Authors
  1. L. Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. W. Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K. Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. X. Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. L. Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conception and design of study: LL, WW and KX. Acquisition of data: LL, WW and KX. Data analysis and/or interpretation: LL and XG. Drafting of manuscript and/or critical revision: LL. Approval of final version of manuscript: all authors.

Corresponding author

Correspondence to L. Zhou.

Ethics declarations

Conflict of interest

All authors have no conflicts of interest or financial ties to disclose.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (XLSX 1821 KB)

Supplementary file2 (DOCX 15 KB)

Supplementary file3 (DOCX 16 KB)

40618_2023_2060_MOESM4_ESM.tiff

Supplementary file4 Scatter plot of the effect of total testosterone level on BPH outcome. BPH: benign prostatic hyperplasia; MR: Mendelian randomization; SNP: single-nucleotide polymorphism (TIFF 1406 KB)

40618_2023_2060_MOESM5_ESM.tiff

Supplementary file5 Scatter plot of the effect of bioavailable testosterone level on BPH outcome. BPH: benign prostatic hyperplasia; MR: Mendelian randomization; SNP: single-nucleotide polymorphism (TIFF 1406 KB)

40618_2023_2060_MOESM6_ESM.tiff

Supplementary file6 Scatter plot of the effect of SHBG level on BPH outcome. SHBG: sex hormone-binding globulin; BPH: benign prostatic hyperplasia; MR: Mendelian randomization; SNP: single-nucleotide polymorphism (TIFF 1406 KB)

40618_2023_2060_MOESM7_ESM.tiff

Supplementary file7 Forest plot of the effect of bioavailable testosterone level on BPH outcome. BPH: benign prostatic hyperplasia; MR: Mendelian randomization (TIFF 2197 KB)

40618_2023_2060_MOESM8_ESM.tiff

Supplementary file8 Leave-one-out sensitive analysis of the effect of bioavailable testosterone level on BPH outcome. BPH: benign prostatic hyperplasia; MR: Mendelian randomization (TIFF 2197 KB)

40618_2023_2060_MOESM9_ESM.tif

Supplementary file9 Bidirectional MR analysis to assess the effect of bioavailable testosterone level on the phenotypes of HDL-C (A), LDL-C (B), triglycerides (C), T2DM (D), hypertension (E) and BMI (F) HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; T2DM: type 2 diabetes mellitus; BMI: body mass index; MR: Mendelian randomization; IVW: inverse variance weighted regression; MR Egger: Egger's regression for Mendelian randomization; CI: confidence interval (TIF 2197 KB)

40618_2023_2060_MOESM10_ESM.tif

Supplementary file10 Bidirectional MR analysis to assess the effect of HDL-C (A), LDL-C (B), triglycerides (C), T2DM (D), hypertension (E) and BMI (F) on bioavailable testosterone level HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; T2DM: type 2 diabetes mellitus; BMI: body mass index; MR: Mendelian randomization; IVW: inverse variance weighted regression; MR Egger: Egger's regression for Mendelian randomization; CI: confidence interval (TIF 2220 KB)

40618_2023_2060_MOESM11_ESM.tif

Supplementary file11 Bidirectional MR analysis to assess the effect of total testosterone level on the phenotypes of HDL-C (A), LDL-C (B), triglycerides (C), T2DM (D), hypertension (E) and BMI (F). HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; T2DM: type 2 diabetes mellitus; BMI: body mass index; MR: Mendelian randomization; IVW: inverse variance weighted regression; MR Egger: Egger's regression for Mendelian randomization; CI: confidence interval (TIF 2258 KB)

40618_2023_2060_MOESM12_ESM.tif

Supplementary file12 Bidirectional MR analysis to assess the effect of HDL-C (A), LDL-C (B), triglycerides (C), T2DM (D), hypertension (E) and BMI (F) on total testosterone level. HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; T2DM: type 2 diabetes mellitus; BMI: body mass index; MR: Mendelian randomization; IVW: inverse variance weighted regression; MR Egger: Egger's regression for Mendelian randomization; CI: confidence interval (TIF 2231 KB)

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

Lin, L., Wang, W., Xiao, K. et al. Genetically elevated bioavailable testosterone level was associated with the occurrence of benign prostatic hyperplasia. J Endocrinol Invest 46, 2095–2102 (2023). https://doi.org/10.1007/s40618-023-02060-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40618-023-02060-0

Keywords

Search

Navigation