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Lower Circulating Androgens Are Associated with Overall Cancer Risk and Prostate Cancer Risk in Men Aged 25–84 Years from the Busselton Health Study

  • Yi X. Chan
  • Matthew W. Knuiman
  • Mark L. Divitini
  • David J. Handelsman
  • John P. Beilby
  • Bu B. Yeap
Original Paper

Abstract

Androgens, notably testosterone (T), have been implicated in development of several common cancers and prostate cancer; however, precise mechanisms remain unclear. This study assessed prospective associations of serum T, dihydrotestosterone (DHT) and estradiol (E2) with overall cancer (excluding skin cancer), prostate, colorectal and lung cancer risk in 1574 community-dwelling men aged 25–84 years. Sex hormones were assayed using mass spectrometry and men were followed for 20 years with outcomes ascertained using data linkage. Over 20 years, there were 289, 116, 48 and 22 men who developed any cancer, prostate cancer, colorectal cancer and lung cancer, respectively. Androgens in the lowest quartile were associated with an increased overall cancer risk (HR = 1.36, 95% CI 1.05–1.76, p = 0.020 for T; and HR = 1.30, 95% CI 1.00–1.69, p = 0.049 for DHT comparing the lowest vs other quartiles). T in the lowest quartile was associated with an increased risk of prostate cancer (HR = 1.53, 95% CI 1.02–2.29, p = 0.038 comparing the lowest vs other quartiles). The association between androgens and overall cancer risk remained similar after excluding prostate cancer outcomes; however, results were not significant. There were no associations of T, DHT or E2 with colorectal or lung cancer risk; however, LH in the highest quartile was associated with an increased risk of lung cancer (HR = 4.55, 95% CI 1.70–12.19, p = 0.003 for the highest vs other quartiles). Whether T is a biomarker of poor health in men with any cancer or prostate cancer requires further confirmation as does the nature and mechanism of the association of a high LH with future lung cancer.

Keywords

Testosterone Dihydrotestosterone Estradiol Cancer incidence 

Notes

Acknowledgements

The authors thank the staff of the Western Australian Data Linkage Branch, the Cancer Registry and the Registrar General’s Office for their assistance in providing linked data. The authors especially thank the Busselton men who took part in the survey and the Busselton Population Medical Research Institute for access to the survey data and specimens.

Funding

This study was funded by Project Grant 1021326 from the National Health and Medical Research Council of Australia. BBY is the recipient of a clinical investigator award from the Sylvia and Charles Viertel Charitable Foundation, NSW, Australia. The 1994/1995 Busselton Health Survey was supported and funded by the Health Promotion Foundation of Western Australia. The funding sources had no involvement in the planning, analysis and writing of the manuscript.

Supplementary material

12672_2018_346_MOESM1_ESM.docx (17 kb)
ESM 1 (DOCX 17 kb)
12672_2018_346_MOESM2_ESM.docx (53 kb)
ESM 2 (DOCX 53 kb)

References

  1. 1.
    International Agency for Research on Cancer, World Cancer Report 2014. International Agency for Research on Cancer, World Health Organisation. Lyon, 2014Google Scholar
  2. 2.
    Sharifi N, Gulley JL, Dahut WL (2010) An update on androgen deprivation therapy for prostate cancer. Endocr Relat Cancer 17:R305–R315CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Endogenous Hormones and Prostate Cancer Collaborative Group (2008) Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies. J Natl Cancer Inst 100:170–183CrossRefPubMedCentralGoogle Scholar
  4. 4.
    Hyde Z, Flicker L, McCaul KA, Almeida OP, Hankey GJ et al (2012) Associations between testosterone levels and incident prostate, lung, and colorectal cancer. A population-based study. Cancer Epidemiol Biomark Prev 21:1319–1329CrossRefGoogle Scholar
  5. 5.
    Chan YX, Alfonso H, Chubb SAP, Handelsman DJ, Fegan PG, Hankey GJ, Golledge J, Flicker L, Yeap BB (2017) Higher dihydrotestosterone is associated with the incidence of lung cancer in older men. Horm Cancer 8:119–126CrossRefPubMedGoogle Scholar
  6. 6.
    Huang R, Wang G, Song Y, Wang F, Zhu B, Tang Q, Liu Z, Chen Y, Zhang Q, Muhammad S, Wang X (2015) Polymorphic CAG repeat and protein expression of androgen receptor gene in colorectal cancer. Mol Cancer Ther 14:1066–1074CrossRefPubMedGoogle Scholar
  7. 7.
    Orsted DD, Nordestgaard BG, Bojesen SE (2014) Plasma testosterone in the general population, cancer prognosis and cancer risk: a prospective cohort study. Ann Oncol 25:712–718CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Shiraishi S, Lee P, Leung A, Goh VHH, Swerdloff RS et al (2008) Simultaneous measurement of serum testosterone and dihydrotestosterone by liquid chromatography-tandem mass spectrometry. Clin Chem 54:1855–1863CrossRefPubMedGoogle Scholar
  9. 9.
    Hsing AW, Stanczyk FZ, Bélanger A, Schroeder P, Chang L et al (2007) Reproducibility of serum sex steroid assays in men by RIA and mass spectrometry. Cancer Epidemiol Biomark Prev 16:1004–1008CrossRefGoogle Scholar
  10. 10.
    Russell DW, Wilson JD (1994) Steroid 5 alpha-reductase: two genes/two enzymes. Annu Rev Biochem 63:25–61CrossRefPubMedGoogle Scholar
  11. 11.
    Longcope C, Kato T, Horton R (1969) Conversion of blood androgens to estrogens in normal adult men and women. J Clin Invest 48:2191–2201CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Muller RL, Gerber L, Moreira DM, Andriole G, Castro-Santamaria R, Freedland SJ (2012) Serum testosterone and dihydrotestosterone and prostate cancer risk in the placebo arm of the Reduction by Dutasteride of Prostate Cancer Events trial. Eur Urol 62:757–764CrossRefPubMedGoogle Scholar
  13. 13.
    Knuiman MW, Jamrozik K, Welborn TA, Bulsara MK, Divitini ML et al (1995) Age and secular trends in risk factors for cardiovascular disease in Busselton. Aust J Public Health 19:375–382CrossRefPubMedGoogle Scholar
  14. 14.
    Knuiman MW, Hung J, Divitini ML, Davis TM, Beilby JP (2009) Utility of the metabolic syndrome and its components in the prediction of incident cardiovascular disease: a prospective cohort study. Eur J Cardiovasc Prev Rehabil 16:235–241CrossRefPubMedGoogle Scholar
  15. 15.
    Prasad MRN, Singh SP, Rajalakshmi M (1970) Fertility control in male rats by continuous release of microquantities of cyproterone acetate from subcutaneous silastic capsules. Contraception 2:165–178CrossRefGoogle Scholar
  16. 16.
    Yeap BB, Knuiman MW, Divitini ML, Handelsman DJ, Beilby JP, Beilin J, McQuillan B, Hung J (2014) Differential associations of testosterone, dihydrotestosterone and oestradiol with physical, metabolic and health-related factors in community-dwelling men aged 17-97 years from the Busselton Health Survey. Clin Endocrinol 81:100–108CrossRefGoogle Scholar
  17. 17.
    Holman CD, Bass AJ, Rosman DL, Smith MB, Semmens JB et al (2008) A decade of data linkage in Western Australia: strategic design, applications and benefits of the WA data linkage system. Aust Health Rev 32:766–777CrossRefPubMedGoogle Scholar
  18. 18.
    Khaw KT, Dowsett M, Folkerd E, Bingham S, Wareham N, Luben R, Welch A, Day N (2007) Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk) Prospective Population Study. Circulation 116:2694–2701CrossRefPubMedGoogle Scholar
  19. 19.
    Haring R, Völzke H, Steveling A, Krebs A, Felix SB et al (2010) Low serum testosterone levels are associated with increased risk of mortality in a population-based cohort of men aged 20-79. Eur Heart J 31:1494–1501CrossRefPubMedGoogle Scholar
  20. 20.
    Araujo AB, Kupelian V, Page ST, Handelsman DJ, Brenner WJ et al (2007) Sex steroids and all-cause and cause-specific mortality in men. Arch Intern Med 167:1252–1260CrossRefPubMedGoogle Scholar
  21. 21.
    Laughlin GA, Barrett-Connor E, Bergstrom J (2008) Low serum testosterone and mortality in older men. J Clin Endocrinol Metab 93:68–75CrossRefPubMedGoogle Scholar
  22. 22.
    Hsu B, Cumming RG, Naganathan V, Blyth FM, Le Couteur DG et al (2016) Temporal changes in androgens and estrogens are associated with all-cause and cause-specific mortality in older men. J Clin Endocrinol Metab 101:2201–2210CrossRefPubMedGoogle Scholar
  23. 23.
    Dev R, Hui D, Fabbro ED, Delgado-Guay MO, Sobti N et al (2014) Association between hypogonadism, symptom burden, and survival in male patients with advanced cancer. Cancer 120:1586–1593CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Burney BO, Hayes TG, Smiechowska J, Cardwell G, Papusha V, Bhargava P, Konda B, Auchus RJ, Garcia JM (2012) Low testosterone levels and increased inflammatory markers in patients with cancer and relationship with cachexia. J Clin Endocrinol Metab 97(5):E700–E709CrossRefPubMedGoogle Scholar
  25. 25.
    Svartberg J, Midtby M, Bønaa KH, Sundsfjord J, Joakimsen RM et al (2003) The associations of age, lifestyle factors and chronic disease with testosterone in men: the Tromso Study. Eur J Endocrinol 149:145–152CrossRefPubMedGoogle Scholar
  26. 26.
    Daniels NA, Nielson CM, Hoffman AR, Bauer DC et al (2010) Sex hormones and the risk of incident prostate cancer. Urology 76:1034–1040CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Morgentaler A, Bruning CO III, DeWolf WC (1996) Occult prostate cancer in men with low serum testosterone levels. JAMA 276:1904–1906CrossRefPubMedGoogle Scholar
  28. 28.
    Hoffman MA, DeWolf WC, Morgentaler A (2000) Is low serum free testosterone a marker for high grade prostate cancer? J Urol 163:824–827CrossRefPubMedGoogle Scholar
  29. 29.
    Schatzl G, Madersbacher S, Thurridl T, Waldmüller J, Kramer G, Haitel A, Marberger M (2001) High-grade prostate cancer is associated with low serum testosterone levels. Prostate 47:52–58CrossRefPubMedGoogle Scholar
  30. 30.
    Llukani E, Katz BF, Agalliu I, Lightfoot A, Yu SS et al (2017) Low levels of serum testosterone in middle-aged men impact pathological features of prostate cancer. Prostate Int 5:17–23CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Massengill JC, Sun L, Moul JW, Wu H, Mcleod DG et al (2003) Pretreatment total testosterone level predicts pathological stage in patients with localized prostate cancer treated with radical prostatectomy. J Urol 169:1670–1675CrossRefPubMedGoogle Scholar
  32. 32.
    Miller LR, Partin AW, Chan DW, Bruzek DJ, Dobs AS et al (1998) Influence of radical prostatectomy on serum hormone levels. J Urol 160:449–453CrossRefPubMedGoogle Scholar
  33. 33.
    Zhang PL, Rosen S, Veeramachaneni R, Kao J, DeWolf WC et al (2002) Association between prostate cancer and serum testosterone levels. Prostate 53:179–182CrossRefPubMedGoogle Scholar
  34. 34.
    Abdelbaset-Ismail A, Pedziwiatr D, Schneider G, Niklinski J, Charkiewicz R, Moniuszko M, Kucia M, Ratajczak MZ (2017) Pituitary sex hormones enhance the prometastatic potential of human lung cancer cells by downregulating the intracellular expression of heme oxygenase1. Int J Oncol 50:317–328CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.The Medical SchoolUniversity of Western AustraliaCrawleyAustralia
  2. 2.Department of Endocrinology and DiabetesFiona Stanley HospitalMurdochAustralia
  3. 3.School of Population and Global HealthUniversity of Western AustraliaCrawleyAustralia
  4. 4.ANZAC Research InstituteUniversity of SydneySydneyAustralia
  5. 5.PathWest Laboratory MedicineSir Charles Gairdner HospitalNedlandsAustralia
  6. 6.School of Pathology and Laboratory MedicineUniversity of Western AustraliaCrawleyAustralia

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