PDF herunterladen
Horm Metab Res 2015; 47(11): 846-854
DOI: 10.1055/s-0034-1395569
Endocrine Care
© Georg Thieme Verlag KG Stuttgart · New York

Total Testosterone and Calculated Estimates for Free and Bioavailable Testosterone: Influence of Age and Body Mass Index and Establishment of Sex-Specific Reference Ranges

T. Deutschbein
1   Department of Internal Medicine I, Endocrine and Diabetes Unit, University Hospital Würzburg, University of Würzburg, Würzburg, Germany
,
K. Mann
2   Department of Endocrinology and Division of Laboratory Research, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
,
S. Petersenn
3   ENDOC Center for Endocrine Tumors, Hamburg, Germany
› Institutsangaben
Weitere Informationen

Publikationsverlauf

received 06. August 2014

accepted 29. Oktober 2014

Publikationsdatum:
07. Januar 2015 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Erratum zu diesem Artikel:

Total Testosterone and Calculated Estimates for Free and Bioavailable Testosterone: Influence of Age and Body Mass Index and Establishment of Sex-Specific Reference RangesHorm Metab Res 2015; 47(11): e5-e5
DOI: 10.1055/s-0035-1548909

Abstract

Measurement of sex steroids is required to evaluate gonadal function, but normative data are lacking (especially for estimates of physiologically active testosterone). Using modern immunoassays, this study established sex-specific reference ranges (2.5% and 97.5% percentiles) for total testosterone (TOT), bioactive testosterone Vermeulen (BTV), free androgen index (FAI), free testosterone Sartorius (FTS), free testosterone Vermeulen (FTV), and sex hormone binding globulin (SHBG). In the comparative study, subjects were grouped by age (18–30; 31–50; >50 years), BMI (<25; 25–30; >30 kg/m2), and sex. Study participants were selected in such a way that each group comprised 12 subjects (e. g., 12 males between 18 and 30 years with a BMI of <25 kg/m2, and so on), resulting in a total of 216 controls (108 males, 108 females; age: 40.3±1.0; BMI: 27.8±0.4). Multiple stepwise regression analyses were performed (covariates: age, BMI, sex), and sex-specific reference ranges were applied to 50 males (age: 46.1±2.3; BMI: 27.4±0.7) with suspected hypogonadism. Regression analysis identified the strongest predictor of each parameter apart from sex, resulting in age-specific (males: FAI, SHBG, BTV, FTV; females: TOT, FTS, SHBG), BMI-specific (males: TOT, FTS; females: FAI, BTV, FTV) and overall cutoffs for both sexes. In male patients, overall agreement between the results derived from the estimates (i. e., BTV, FTS, FTV) was high (with discordant results in only 4%). In summary, if both the endocrine workup and the clinical presentation were taken into account, the newly established reference ranges allowed reliable identification of hypogonadal males.

Key words

hyperandrogenemia - hypogonadism - impaired fertility - lower limit of normal - multiple stepwise regression analysis - polycystic ovary syndrome - upper limit of normal
 

  • References

  • 1 The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group Revised . 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004; 19: 41-47
    CrossrefPubMedSuche in Google Scholar
  • 2 Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM. Task Force, Endocrine Society. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010; 95: 2536-2559
    CrossrefPubMedSuche in Google Scholar
  • 3 Hammond GL, Wu TS, Simard M. Evolving utility of sex hormone-binding globulin measurements in clinical medicine. Curr Opin Endocrinol Diabetes Obes 2012; 19: 183-189
    CrossrefPubMedSuche in Google Scholar
  • 4 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: 405-413
    CrossrefPubMedSuche in Google Scholar
  • 5 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: 3666-3672
    CrossrefPubMedSuche in Google Scholar
  • 6 Sartorius G, Ly LP, Sikaris K, McLachlan R, Handelsman DJ. Predictive accuracy and sources of variability in calculated free testosterone estimates. Ann Clin Biochem 2009; 46 (Pt 2) 137-143
    CrossrefPubMedSuche in Google Scholar
  • 7 Södergård R, Bäckström T, Shanbhag V, Carstensen H. Calculation of free and bound fractions of testosterone and estradiol-17 beta to human plasma proteins at body temperature. J Steroid Biochem 1982; 16: 801-810
    CrossrefPubMedSuche in Google Scholar
  • 8 Ly LP, Handelsman DJ. Empirical estimation of free testosterone from testosterone and sex hormone-binding globulin immunoassays. Eur J Endocrinol 2005; 152: 471-478
    CrossrefPubMedSuche in Google Scholar
  • 9 Emadi-Konjin P, Bain J, Bromberg IL. Evaluation of an algorithm for calculation of serum “bioavailable” testosterone (BAT). Clin Biochem 2003; 36: 591-596
    CrossrefPubMedSuche in Google Scholar
  • 10 Morris PD, Malkin CJ, Channer KS, Jones TH. A mathematical comparison of techniques to predict biologically available testosterone in a cohort of 1072 men. Eur J Endocrinol 2004; 151: 241-249
    CrossrefPubMedSuche in Google Scholar
  • 11 Nanjee MN, Wheeler MJ. Plasma free testosterone – is an index sufficient?. Ann Clin Biochem 1985; 22 (Pt 4) 387-390
    CrossrefPubMedSuche in Google Scholar
  • 12 Leifke E, Gorenoi V, Wichers C, von zur Mühlen A, von Büren E, Brabant G. Age-related changes of serum sex hormones, insulin-like growth factor-1 and sex-hormone binding globulin levels in men: cross-sectional data from a healthy male cohort. Clin Endocrinol (Oxf) 2000; 53: 689-695
    CrossrefPubMedSuche in Google Scholar
  • 13 Elmlinger MW, Dengler T, Weinstock C, Kuehnel W. Endocrine Alterations in the Aging Male. Clin Chem Lab Med 2003; 41: 934-941
    CrossrefPubMedSuche in Google Scholar
  • 14 de Ronde W, van der Schouw YT, Pols HA, Gooren LJ, Muller M, Grobbee DE, de Jong FH. Calculation of bioavailable and free testosterone in men: a comparison of 5 published algorithms. Clin Chem 2006; 52: 1777-1784
    CrossrefPubMedSuche in Google Scholar
  • 15 Giton F, Urien S, Born C, Tichet J, Guéchot J, Callebert J, Bronsard F, Raynaud JP, Fiet J. Determination of bioavailable testosterone [non sex hormone binding globulin (SHBG)-bound testosterone] in a population of healthy French men: influence of androstenediol on testosterone binding to SHBG. Clin Chem 2007; 53: 2160-2168
    CrossrefPubMedSuche in Google Scholar
  • 16 Shiraishi S, Lee PW, Leung A, Goh VH, Swerdloff RS, Wang C. Simultaneous measurement of serum testosterone and dihydrotestosterone by liquid chromatography-tandem mass spectrometry. Clin Chem 2008; 54: 1855-1863
    CrossrefPubMedSuche in Google Scholar
  • 17 Kushnir MM, Blamires T, Rockwood AL, Roberts WL, Yue B, Erdogan E, Bunker AM, Meikle AW. Liquid chromatography tandem mass spectrometry assay for androstenedione, dehydroepiandrosterone, and testosterone with pediatric and adult reference intervals. Clin Chem 2010; 56: 1138-1147
    CrossrefPubMedSuche in Google Scholar
  • 18 Bhasin S, Pencina M, Jasuja GK, Travison TG, Coviello A, Orwoll E, Wang PY, Nielson C, Wu F, Tajar A, Labrie F, Vesper H, Zhang A, Ulloor J, Singh R, Dagostino R, Vasan RS. Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham Heart Study and applied to three geographically distinct cohorts. J Clin Endocrinol Metab 2011; 96: 2430-2439
    CrossrefPubMedSuche in Google Scholar
  • 19 Fanelli F, Belluomo I, Di Lallo VD, Cuomo G, De Iasio R, Baccini M, Casadio E, Casetta B, Vicennati V, Gambineri A, Grossi G, Pasquali R, Pagotto U. Serum steroid profiling by isotopic dilution-liquid chromatography-mass spectrometry: comparison with current immunoassays and reference intervals in healthy adults. Steroids 2011; 76: 244-253
    CrossrefPubMedSuche in Google Scholar
  • 20 Neale SM, Hocking R, Biswas M, Turkes A, Rees D, Rees DA, Evans C. Adult testosterone and calculated free testosterone reference ranges by tandem mass spectrometry. Ann Clin Biochem 2013; 50: 159-161
    CrossrefPubMedSuche in Google Scholar
  • 21 Kelleher S, Conway AJ, Handelsman DJ. Blood testosterone threshold for androgen deficiency symptoms. J Clin Endocrinol Metab 2004; 89: 3813-3817
    CrossrefPubMedSuche in Google Scholar
  • 22 Schatzl G, Madersbacher S, Temml C, Krenn-Schinkel K, Nader A, Sregi G, Lapin A, Hermann M, Berger P, Marberger M. Serum androgen levels in men: impact of health status and age. Urology 2003; 61: 629-633
    CrossrefPubMedSuche in Google Scholar
  • 23 Mohr BA, Guay AT, O’Donnell AB, McKinlay JB. Normal, bound and nonbound testosterone levels in normally ageing men: results from the Massachusetts Male Ageing Study. Clin Endocrinol (Oxf) 2005; 62: 64-73
    CrossrefPubMedSuche in Google Scholar
  • 24 Pesant MH, Desmarais G, Fink GD, Baillargeon JP. Reference ranges for total and calculated free and bioavailable testosterone in a young healthy women population with normal menstrual cycles or using oral contraception. Clin Biochem 2012; 45: 148-150
    CrossrefPubMedSuche in Google Scholar
  • 25 Haring R, Hannemann A, John U, Radke D, Nauck M, Wallaschofski H, Owen L, Adaway J, Keevil BG, Brabant G. Age-specific reference ranges for serum testosterone and androstenedione concentrations in women measured by liquid chromatography-tandem mass spectrometry. J Clin Endocrinol Metab 2012; 97: 408-415
    CrossrefPubMedSuche in Google Scholar
  • 26 Hahn S, Kuehnel W, Tan S, Kramer K, Schmidt M, Roesler S, Kimmig R, Mann K, Janssen OE. Diagnostic value of calculated testosterone indices in the assessment of polycystic ovary syndrome. Clin Chem Lab Med 2007; 45: 202-207
    PubMedSuche in Google Scholar
  • 27 Kushnir MM, Blamires T, Rockwood AL, Roberts WL, Yue B, Erdogan E, Bunker AM, Meikle AW. Liquid chromatography tandem mass spectrometry assay for androstenedione, dehydroepiandrosterone, and testosterone with pediatric and adult reference intervals. Clin Chem 2010; 56: 1138-1147
    CrossrefPubMedSuche in Google Scholar
  • 28 Salameh WA, Redor-Goldman MM, Clarke NJ, Reitz RE, Caulfield MP. Validation of a total testosterone assay using high-turbulence liquid chromatography tandem mass spectrometry: total and free testosterone reference ranges. Steroids 2010; 75: 169-175
    CrossrefPubMedSuche in Google Scholar
  • 29 Haslam S, Hunt N, Myers M. Determining calculated free testosterone reference intervals in a normal adult male population. Clin Chem Lab Med 2013; 51: e209-e211
    PubMedSuche in Google Scholar
  • 30 Andersson AM, Jensen TK, Juul A, Petersen JH, Jørgensen T, Skakkebaek NE. Secular decline in male testosterone and sex hormone binding globulin serum levels in Danish population surveys. J Clin Endocrinol Metab 2007; 92: 4696-4705
    CrossrefPubMedSuche in Google Scholar
  • 31 Davison SL, Bell R, Donath S, Montalto JG, Davis SR. Androgen levels in adult females: changes with age, menopause, and oophorectomy. J Clin Endocrinol Metab 2005; 90: 3847-3853
    CrossrefPubMedSuche in Google Scholar
  • 32 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: 5928-5936
    CrossrefPubMedSuche in Google Scholar
  • 33 Moal V, Mathieu E, Reynier P, Malthièry Y, Gallois Y. Low serum testosterone assayed by liquid chromatography-tandem mass spectrometry. Comparison with five immunoassay techniques. Clin Chim Acta 2007; 386: 12-19
    CrossrefPubMedSuche in Google Scholar
  • 34 Huhtaniemi IT, Tajar A, Lee DM, O’Neill TW, Finn JD, Bartfai G, Boonen S, Casanueva FF, Giwercman A, Han TS, Kula K, Labrie F, Lean ME, Pendleton N, Punab M, Silman AJ, Vanderschueren D, Forti G, Wu FC. EMAS Group . 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: 983-991
    CrossrefPubMedSuche in Google Scholar
  • 35 Vesper HW, Bhasin S, Wang C, Tai SS, Dodge LA, Singh RJ, Nelson J, Ohorodnik S, Clarke NJ, Salameh WA, Parker Jr CR, Razdan R, Monsell EA, Myers GL. Interlaboratory comparison study of serum total testosterone measurements performed by mass spectrometry methods. Steroids 2009; 74: 498-503
    CrossrefPubMedSuche in Google Scholar
  • 36 Handelsman DJ, Wartofsky L. Requirement for mass spectrometry sex steroid assays in the Journal of Clinical Endocrinology and Metabolism. J Clin Endocrinol Metab 2013; 98: 3971-3973
    CrossrefPubMedSuche in Google Scholar