Abstract
Background:
The total testosterone (T) cutoffs clinically adopted to define late-onset hypogonadism (LOH) do not consider the differences that exist between different analytical platforms, nor do they consider the body mass index (BMI) or age of the patient. We aimed at providing method, age and BMI-specific normal values for total T in European healthy men.
Methods:
A total of 351 eugonadal healthy men were recruited, and total T was measured with four automated immunometric assays (IMAs): ARCHITECT i1000SR (Abbott), UniCel DxI800 (Beckman Coulter), Cobas e601 (Roche), IMMULITE 2000 (Siemens) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Reference ranges (RRs) were calculated for each method.
Results:
Passing and Bablok regression analysis and Bland-Altman plot showed an acceptable agreement between Abbott and LC-MS/MS, but a poor one between LC-MS/MS and the other IMAs. Age-specific T concentrations in non-obese (BMI <29.9 kg/m2) men were greater than in all men. The total T normal range, in non-obese men aged 18–39 years, measured with LC-MS/MS was 9.038–41.310 nmol/L. RRs calculated with LC-MS/MS statistically differed from the ones calculated with all individual IMAs, except Abbott and among all IMAs. Statistically significant differences for both upper and lower reference limits between our RRs and the ones provided by the manufacturers were also noticed.
Conclusions:
We calculated normal ranges in a non-obese cohort of European men, aged 18–39 years, with four commercially available IMAs and LC-MS/MS and found statistically significant differences according to the analytical method used. Method-specific reference values can increase the accuracy of LOH diagnosis and should be standardly used.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Vesper HW, Botelho JC, Wang Y. Challenges and improvements in testosterone and estradiol testing. Asian J Androl 2014;16:178–84.10.4103/1008-682X.122338Search in Google Scholar PubMed PubMed Central
2. Harman SM. Testosterone in older men after the Institute of Medicine Report: where do we go from here? Climacteric 2005;8:124–35.10.1080/13697130500118001Search in Google Scholar PubMed
3. Kaufman JM, Vermeulen A. The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev 2005;26:833–76.10.1210/er.2004-0013Search in Google Scholar PubMed
4. Stellato RK, Feldman HA, Hamdy O, Horton ES, McKinlay JB. Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts male aging study. Diabetes Care 2000;23:490–4.10.2337/diacare.23.4.490Search in Google Scholar PubMed
5. Wittert G. The relationship between sleep disorders and testosterone in men. Asian J Androl 2014;16:262–5.10.4103/1008-682X.122586Search in Google Scholar PubMed PubMed Central
6. Wang C, Jackson G, Jones TH, Matsumoto AM, Nehra A, Perelman MA, et al. Low testosterone associated with obesity and the metabolic syndrome contributes to sexual dysfunction and cardiovascular disease risk in men with type 2 diabetes. Diabetes Care 2011;34:1669–75.10.2337/dc10-2339Search in Google Scholar PubMed PubMed Central
7. Oskui PM, French WJ, Herring MJ, Mayeda GS, Burstein S, Kloner RA. Testosterone and the cardiovascular system: a comprehensive review of the clinical literature. J Am Heart Assoc 2013;2:e000272.10.1161/JAHA.113.000272Search in Google Scholar PubMed PubMed Central
8. Wu FC, Tajar A, Pye SR, Silman AJ, Finn JD, O’Neill TW, et al. Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European Male Aging Study. J Clin Endocrinol Metab 2008;93:2737–45.10.1210/jc.2007-1972Search in Google Scholar PubMed
9. Lombardo F, Sgro P, Salacone P, Gilio B, Gandini L, Dondero F, et al. Androgens and fertility. J Endocrinol Invest 2005;28(3 Suppl):51–5.10.1111/j.1365-2605.2005.00585.xSearch in Google Scholar PubMed
10. Moskovic DJ, Araujo AB, Lipshultz LI, Khera M. The 20-year public health impact and direct cost of testosterone deficiency in U.S. men. J Sex Med 2013;10:562–9.10.1111/j.1743-6109.2012.02944.xSearch in Google Scholar PubMed
11. Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR, Baltimore Longitudinal Study of Aging. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 2001;86:724–31.10.1210/jcem.86.2.7219Search in Google Scholar PubMed
12. Feldman HA, Longcope C, Derby CA, Johannes CB, Araujo AB, Coviello AD, et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab 2002;87:589–98.10.1210/jcem.87.2.8201Search in Google Scholar PubMed
13. Travison TG, Araujo AB, Kupelian V, O’Donnell AB, McKinlay JB. The relative contributions of aging, health, and lifestyle factors to serum testosterone decline in men. J Clin Endocrinol Metab 2007;92:549–55.10.1210/jc.2006-1859Search in Google Scholar PubMed
14. Corona G, Monami M, Rastrelli G, Aversa A, Tishova Y, Saad F, et al. Testosterone and metabolic syndrome: a meta-analysis study. J Sex Med 2011;8:272–83.10.1111/j.1743-6109.2010.01991.xSearch in Google Scholar PubMed
15. Muller M, den Tonkelaar I, Thijssen JH, Grobbee DE, van der Schouw YT. Endogenous sex hormones in men aged 40–80 years. Eur J Endocrinol 2003;149:583–9.10.1530/eje.0.1490583Search in Google Scholar PubMed
16. Wu FC. Commentary: guideline for male testosterone therapy: a European perspective. J Clin Endocrinol Metab 2007;92:418–9.10.1210/jc.2006-2799Search in Google Scholar PubMed
17. Shames D, Gassman A, Handelsman H. Commentary: guideline for male testosterone therapy: a regulatory perspective. J Clin Endocrinol Metab 2007;92:414–5.10.1210/jc.2006-2642Search in Google Scholar PubMed
18. Foresta C, Calogero AE, Lombardo F, Lenzi A, Ferlin A. Late-onset hypogonadism: beyond testosterone. Asian J Androl 2015;17:236–8.10.4103/1008-682X.135985Search in Google Scholar PubMed PubMed Central
19. Neaves WB, Johnson L, Porter JC, Parker CR, Jr., Petty CS. Leydig cell numbers, daily sperm production, and serum gonadotropin levels in aging men. J Clin Endocrinol Metab 1984;59:756–63.10.1210/jcem-59-4-756Search in Google Scholar PubMed
20. Landry D, Cloutier F, Martin LJ. Implications of leptin in neuroendocrine regulation of male reproduction. Reprod Biol 2013; 13:1–14.10.1016/j.repbio.2012.12.001Search in Google Scholar PubMed
21. Mah PM, Wittert GA. Obesity and testicular function. Mol Cell Endocrinol 2010;316:180–6.10.1016/j.mce.2009.06.007Search in Google Scholar PubMed
22. Spitzer M, Huang G, Basaria S, Travison TG, Bhasin S. Risks and benefits of testosterone therapy in older men. Nat Rev Endocrinol 2013;9:414–24.10.1038/nrendo.2013.73Search in Google Scholar PubMed
23. Baillargeon J, Urban RJ, Ottenbacher KJ, Pierson KS, Goodwin JS. Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Intern Med 2013;173:1465–6.10.1001/jamainternmed.2013.6895Search in Google Scholar PubMed PubMed Central
24. Handelsman DJ. Global trends in testosterone prescribing, 2000–2011: expanding the spectrum of prescription drug misuse. Med J Aust 2013;199:548–51.10.5694/mja13.10111Search in Google Scholar PubMed
25. Nguyen CP, Hirsch MS, Moeny D, Kaul S, Mohamoud M, Joffe HV. Testosterone and “Age-Related Hypogonadism” – FDA Concerns. N Engl J Med 2015;373:689–91.10.1056/NEJMp1506632Search in Google Scholar PubMed PubMed Central
26. Busnelli A, Somigliana E, Vercellini P. ‘Forever Young’-Testosterone replacement therapy: a blockbuster drug despite flabby evidence and broken promises. Hum Reprod 2017;32:719–24.10.1093/humrep/dex032Search in Google Scholar PubMed
27. Wu FC, Tajar A, Beynon JM, Pye SR, Silman AJ, Finn JD, et al. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med 2010;363:123–35.10.1056/NEJMoa0911101Search in Google Scholar PubMed
28. Rosner W, Auchus RJ, Azziz R, Sluss PM, Raff H. Position statement: utility, limitations, and pitfalls in measuring testosterone: an endocrine society position statement. J Clin Endocrinol Metab 2007;92:405–13.10.1210/jc.2006-1864Search in Google Scholar PubMed
29. Paduch DA, Brannigan RE, Fuchs EF, Kim ED, Marmar JL, Sandlow JI. The laboratory diagnosis of testosterone deficiency. Urology 2014;83:980–8.10.1016/j.urology.2013.12.024Search in Google Scholar PubMed
30. Le M, Flores D, May D, Gourley E, Nangia AK. Current practices of measuring and reference range reporting of free and total testosterone in the United States. J Urol 2016;195:1556–61.10.1016/j.juro.2015.12.070Search in Google Scholar PubMed
31. Sikaris K, McLachlan RI, Kazlauskas R, de Kretser D, Holden CA, Handelsman DJ. Reproductive hormone reference intervals for healthy fertile young men: evaluation of automated platform assays. J Clin Endocrinol Metab 2005;90:5928–36.10.1210/jc.2005-0962Search in Google Scholar
32. Wang C, Catlin DH, Demers LM, Starcevic B, Swerdloff RS. Measurement of total serum testosterone in adult men: comparison of current laboratory methods versus liquid chromatography-tandem mass spectrometry. J Clin Endocrinol Metab 2004;89: 534–43.10.1210/jc.2003-031287Search in Google Scholar
33. Rosner W, Vesper H, Endocrine Society, American Association for Clinical Chemistry, American Association of Clinical Endocrinologists, Androgen Excess/PCOS Society, et al. Toward excellence in testosterone testing: a consensus statement. J Clin Endocrinol Metab 2010;95:4542–8.10.1210/jc.2010-1314Search in Google Scholar
34. Wang C, Nieschlag E, Swerdloff RS, Behre H, Hellstrom WJ, Gooren LJ, et al. ISA, ISSAM, EAU, EAA and ASA recommendations: investigation, treatment and monitoring of late-onset hypogonadism in males. Aging Male 2009;12:5–12.10.1080/13685530802389628Search in Google Scholar
35. Nieschlag E, Swerdloff R, Behre HM, Gooren LJ, Kaufman JM, Legros JJ, et al. Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, and EAU recommendations. J Androl 2006;27:135–7.10.2164/jandrol.05047Search in Google Scholar
36. Bhasin S, Basaria S. Diagnosis and treatment of hypogonadism in men. Best Pract Res Clin Endocrinol Metab 2011;25:251–70.10.1016/j.beem.2010.12.002Search in Google Scholar
37. Travison TG, Vesper HW, Orwoll E, Wu F, Kaufman JM, Wang Y, et al. Harmonized reference ranges for circulating testosterone levels in men of four cohort studies in the United States and Europe. J Clin Endocrinol Metab 2017;102:1161–73.10.1210/jc.2016-2935Search in Google Scholar
38. Huhtaniemi IT, Tajar A, Lee DM, O’Neill TW, Finn JD, Bartfai G, et al. Comparison of serum testosterone and estradiol measurements in 3174 European men using platform immunoassay and mass spectrometry; relevance for the diagnostics in aging men. Eur J Endocrinol 2012;166:983–91.10.1530/EJE-11-1051Search in Google Scholar
39. Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A. The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 1997;49:822–30.10.1016/S0090-4295(97)00238-0Search in Google Scholar
40. Travison TG, Morley JE, Araujo AB, O’Donnell AB, McKinlay JB. The relationship between libido and testosterone levels in aging men. J Clin Endocrinol Metab 2006;91:2509–13.10.1210/jc.2005-2508Search in Google Scholar PubMed
41. Institute CaLS. Measurement Procedure Comparison and Bias Estimation Using Patient samples; approved guidelines, 3rd ed. ISBN 1-56238-888-6 (Electronic); CLSI Document EP9-A3, 2013. Available at: https://clsi.org/media/1435/ep09a3_sample.pdf.Search in Google Scholar
42. Clinical and Laboratory Standards Institute (CLSI). Defining E, and Verifying Reference Intervals in the Clinical Laboratory. Approved guideline-third Edition. CLSI Document EP28-A3C. Horowitz, GL: CLSI, 2010. Available at: https://clsi.org/media/1421/ep28a3c_sample.pdf.Search in Google Scholar
43. Taieb J, Mathian B, Millot F, Patricot MC, Mathieu E, Queyrel N, et al. Testosterone measured by 10 immunoassays and by isotope-dilution gas chromatography-mass spectrometry in sera from 116 men, women, and children. Clin Chem 2003;49:1381–95.10.1373/49.8.1381Search in Google Scholar PubMed
44. Mohr BA, Bhasin S, Link CL, O’Donnell AB, McKinlay JB. The effect of changes in adiposity on testosterone levels in older men: longitudinal results from the Massachusetts Male Aging Study. Eur J Endocrinol 2006;155:443–52.10.1530/eje.1.02241Search in Google Scholar PubMed
45. Matsumoto AM, Bremner WJ. Serum testosterone assays– accuracy matters. J Clin Endocrinol Metab 2004;89:520–4.10.1210/jc.2003-032175Search in Google Scholar PubMed
46. Orwoll ES, Nielson CM, Labrie F, Barrett-Connor E, Cauley JA, Cummings SR, et al. Evidence for geographical and racial variation in serum sex steroid levels in older men. J Clin Endocrinol Metab 2010;95:E151–60.10.1210/jc.2009-2435Search in Google Scholar PubMed PubMed Central
47. Vesper HW, Wang Y, Vidal M, Botelho JC, Caudill SP. Serum total testosterone concentrations in the US Household Population from the NHANES 2011–2012 study population. Clin Chem 2015;61:1495–504.10.1373/clinchem.2015.245969Search in Google Scholar PubMed PubMed Central
48. Eisenhofer G, Peitzsch M, Kaden D, Langton K, Pamporaki C, Masjkur J, et al. Reference intervals for plasma concentrations of adrenal steroids measured by LC-MS/MS: impact of gender, age, oral contraceptives, body mass index and blood pressure status. Clin Chim Acta 2017;470:115–24.10.1016/j.cca.2017.05.002Search in Google Scholar PubMed PubMed Central
49. Huhtaniemi I. Late-onset hypogonadism: current concepts and controversies of pathogenesis, diagnosis and treatment. Asian J Androl 2014;16:192–202.10.4103/1008-682X.122336Search in Google Scholar PubMed PubMed Central
50. Layton JB, Li D, Meier CR, Sharpless JL, Stürmer T, Jick SS, et al. Testosterone lab testing and initiation in the United Kingdom and the United States, 2000 to 2011. J Clin Endocrinol Metab 2014;99:835–42.10.1210/jc.2013-3570Search in Google Scholar PubMed PubMed Central
51. Araujo AB, Esche GR, Kupelian V, O’Donnell AB, Travison TG, Williams RE, et al. Prevalence of symptomatic androgen deficiency in men. J Clin Endocrinol Metab 2007;92:4241–7.10.1210/jc.2007-1245Search in Google Scholar PubMed
52. Elsherbiny A, Tricomi M, Bhatt D, Dandapantula HK. State-of- the-art: a review of cardiovascular effects of testosterone replacement therapy in adult males. Curr Cardiol Rep 2017;19:35.10.1007/s11886-017-0838-xSearch in Google Scholar PubMed
53. Snyder PJ, Bhasin S, Cunningham GR, Matsumoto AM, Stephens-Shields AJ, Cauley JA, et al. Effects of testosterone treatment in older men. N Engl J Med 2016;374:611–24.10.1056/NEJMoa1506119Search in Google Scholar PubMed PubMed Central
54. Orwoll ES. Establishing a framework–does testosterone supplementation help older men? N Engl J Med 2016;374:682–3.10.1056/NEJMe1600196Search in Google Scholar PubMed
55. FDA briefing document for the joint meeting for Bone, Reproductive, and Urologic Drugs Advisory Committee (BRUDAC) and Drug Safety and Risk Management Advisory Committee (DSARMAC). Silver Sring, MD: FDA Advisory Committee, 17 Sep 2014. Available at: http://www.dfda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM412536.pdf?.Search in Google Scholar
56. Cunningham GR, Toma SM. Clinical review: why is androgen replacement in males controversial? J Clin Endocrinol Metab 2011;96:38–52.10.1210/jc.2010-0266Search in Google Scholar PubMed
57. Swerdloff RS, Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto AM, et al. Long-term pharmacokinetics of transdermal testosterone gel in hypogonadal men. J Clin Endocrinol Metab 2000;85:4500–10.10.1210/jc.85.12.4500Search in Google Scholar
Supplementary Material:
The online version of this article offers supplementary material (https://doi.org/10.1515/cclm-2017-1201).
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