Low free testosterone is associated with hypogonadal signs and symptoms in men with normal total testosterone

Journal of Clinical Endocrinology and Metabolism

Volumn 101, Issue 7, 2016, Pages 2647-2657

  Antonio, Leen ^a,b   Wu, Frederick C W ^c,d   O'Neill, Terence W ^c,e   Pye, Stephen R ^c   Ahern, Tomas B ^c   Laurent, Michaël R ^a   Huhtaniemi, Ilpo T ^f,g   Lean, Michael E J ^h   Keevil, Brian G ⁱ   Rastrelli, Giulia ^j   Forti, Gianni ^j   Bartfai, György ^k   Casanueva, Felipe F ^l   Kula, Krzysztof ^m   Punab, Margus ⁿ   Giwercman, Aleksander ^o   Claessens, Frank ^a   Decallonne, Brigitte ^a,b   Vanderschueren, Dirk ^a,b  

^a UNIVERSITY OF LEUVEN   (Belgium)

^b UNIVERSITY HOSPITALS LEUVEN   (Belgium)

^c UNIVERSITY OF MANCHESTER   (United Kingdom)

^d MANCHESTER ROYAL INFIRMARY   (United Kingdom)

^e UNIVERSITY OF MANCHESTER   (United Kingdom)

^f IMPERIAL COLLEGE LONDON   (United Kingdom)

^g UNIVERSITY OF TURKU   (Finland)

^h UNIVERSITY OF GLASGOW   (United Kingdom)

ⁱ MANCHESTER UNIVERSITY NHS FOUNDATION TRUST   (United Kingdom)

^j UNIVERSITY OF FLORENCE   (Italy)

^k UNIVERSITY OF SZEGED   (Hungary)

^l HOSPITAL CLÍNICO UNIVERSITARIO   (Spain)

^m MEDICAL UNIVERSITY OF LODZ   (Poland)

ⁿ TARTU UNIVERSITY CLINICS   (Estonia)

^o LUND UNIVERSITY   (Sweden)

more..

Author keywords

[No Author keywords available]

Indexed keywords

ANDROGEN; HEMOGLOBIN; SEX HORMONE BINDING GLOBULIN; TESTOSTERONE;

ADULT; AGE; AGED; ANDROGEN DEFICIENCY; ARTICLE; BODY MASS; BONE RADIOGRAPHY; CLINICAL FEATURE; COMORBIDITY; CONTROLLED STUDY; DISEASE ASSOCIATION; ECHOGRAPHY; HEALTH STATUS; HEMOGLOBIN BLOOD LEVEL; HUMAN; HYPOGONADISM; MALE; MEN'S HEALTH; OBESITY; PRIORITY JOURNAL; SEXUAL DYSFUNCTION; SYMPTOMATOLOGY; TESTOSTERONE BLOOD LEVEL; ASYMPTOMATIC DISEASE; BLOOD; CARDIOVASCULAR DISEASE; CAUSE OF DEATH; CLINICAL TRIAL; COHORT ANALYSIS; COMPLICATION; DEFICIENCY; METABOLIC SYNDROME X; METABOLISM; MIDDLE AGED; MORTALITY; MULTICENTER STUDY;

ADULT; AGED; ASYMPTOMATIC DISEASES; CARDIOVASCULAR DISEASES; CAUSE OF DEATH; COHORT STUDIES; HUMANS; HYPOGONADISM; MALE; METABOLIC SYNDROME X; MIDDLE AGED; SEX HORMONE-BINDING GLOBULIN; TESTOSTERONE;

EID: 84978079951     PISSN: 0021972X     EISSN: 19457197     Source Type: Journal    
DOI: 10.1210/jc.2015-4106     Document Type: Article

References (44)

1. Hammond GL, Wu TS, Simard M. Evolving utility of sex hormone-binding globulin measurements in clinical medicine. Curr Opin En-docrinol Diabetes Obesity. 2012;19:183-189.
2. 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.
3. Wu FC, Tajar A, Pye SR, 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 En-docrinol Metab. 2008;93:2737-2745.
4. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes:anEndocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95:2536-2559.
5. Wang C, Nieschlag E, Swerdloff R, et al. Investigation, treatment and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA and ASA recommendations. Eur J Endocrinol. 2008; 159:507-514.
6. 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.
7. Vermeulen A, Stoica T, Verdonck L. The apparent free testosterone concentration, an index of androgenicity. J Clin Endocrinol Metab. 1971;33:759-767.
8. Fiers T, Kaufman JM. Management of hypogonadism: is there a role for salivary testosterone. Endocrine. 2015;50:1-3.
9. Lee DM, O'Neill TW, Pye SR, et al. The European Male Ageing Study (EMAS): design, methods and recruitment. Inte J Androl. 2009;32:11-24.
10. Gallagher LM, Owen LJ, Keevil BG. Simultaneous determination of androstenedione and testosterone in human serum by liquid chro-matography-tandem mass spectrometry. Ann Clin Biochem. 2007; 44:48-56.
11. Labrie F, Belanger A, Belanger P, et al. Androgen glucuronides, instead of testosterone, as the new markers of androgenic activity in women. J Steroid Biochem Mole Biol. 2006;99:182-188.
12. Van Pottelbergh I, Goemaere S, Kaufman JM. Bioavailable estradiol and an aromatase gene polymorphism are determinants of bone mineral density changes in men over 70 years of age. J Clin Endo-crinol Metab. 2003;88:3075-3081.
13. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412-419.
14. Reuben DB, Siu AL. An objective measure of physical function of elderly outpatients. The Physical Performance Test. J Am Geriatr Soc. 1990;38:1105-1112.
15. Siri WE. Body composition from fluid spaces and density: analysis ofmethods. In: Brozek J, Henzchel A, eds. Techniquesfor Measuring Body Composition. Washington, DC: National Academy of Sciences; 1961:224-244.
16. Lean ME, Han TS, Deurenberg P. Predicting body composition by densitometry from simple anthropometric measurements. Am J Clin Nutrition. 1996;63:4-14.
17. O'Connor DB, Corona G, Forti G, et al. Assessmentofsexual health inaging meninEurope: developmentand validationofthe European Male Ageing Study sexual function questionnaire. J Sex Med. 2008; 5:1374-1385.
18. Ware JE, Jr., Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care. 1992;30:473-483.
19. Beck AT, Steer RA, Brown G. Manual for the Beck Depression Inventory-II. San Antonio, TX; 1996.
20. Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120:1640-1645.
21. Moayyeri A, Adams JE, Adler RA, et al. Quantitative ultrasound of the heel and fracture risk assessment: an updated meta-analysis. Osteopor I Int. 2012;23:143-153.
22. Boonen S, Pye SR, O'Neill TW, et al. Influence of bone remodelling rate on quantitative ultrasound parameters at the calcaneus and DXA BMDa of the hip and spine in middle-aged and elderly European men: the European Male Ageing Study (EMAS). Eur J Endo-crinol. 2011;165:977-986.
23. Wu FC, Tajar A, Beynon JM, et al. Identification of late-onset hy-pogonadism in middle-aged and elderly men. N Engl J Med. 2010; 363:123-135.
24. Vermeulen A. Hormonal cut-offs of partial androgen deficiency: a survey of androgen assays. J Endocrinol Invest. 2005;28:28-31.
25. Araujo AB, Esche GR, Kupelian V, et al. Prevalence of symptomatic androgen deficiency in men. J Clin Endocrinol Metab. 2007;92: 4241-4247.
26. Anawalt BD, Hotaling JM, Walsh TJ, Matsumoto AM. Performance of total testosterone measurementtopredict free testosterone for the biochemical evaluationofmale hypogonadism.J Urol. 2012; 187:1369-1373.
27. Cunningham GR, Stephens-Shields AJ, Rosen RC, et al. Association of sex hormones with sexual function, vitality, and physical function of symptomatic older men with low testosterone levels at baseline in the testosterone trials. J Clin Endocrinol Metab. 2015;100:1146-1155.
28. Hsu B, Cumming RG, Blyth FM, et al. The longitudinal relationship of sexual function and androgen status in older men: the Concord Health and Ageing in Men Project. J Clin Endocrinol Metab. 2015; 100:1350-1358.
29. Hyde Z, Flicker L, Hankey GJ, et al. Prevalenceofsexualactivity and associated factors in men aged 75 to 95 years: a cohort study. Ann I Intern Med. 2010;153:693-702.
30. 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; 92:549-555.
31. Camacho EM, Huhtaniemi IT, O'Neill TW, et al. Age-associated changes in hypothalamic-pituitary-testicular function in middle-aged and older men are modified by weight change and lifestyle factors: longitudinal results from the European Male Ageing Study. Eur J Endocrinol. 2013;168:445-455.
32. Antonio L, Wu FC, O'Neill TW, et al. Associations between sex steroids andthe developmentofmetabolic syndrome:Alongitudinal study in European men. J Clin Endocrinol Metab 2015;100:1396-1404.
33. Rastrelli G, Carter EL, Ahern T, et al. Development of and recovery from secondary hypogonadism in aging men: prospective results from the EMAS. J Clin Endocrinol Metab. 2015;100:3172-3182.
34. Vermeulen A, Kaufman JM, Giagulli VA. Influence of some biological indexes on sex hormone-binding globulin and androgen levels in aging or obese males. J Clin Endocrinol Metab. 1996;81:1821-1826.
35. Liao CH, Li HY, Yu HJ, Chiang HS, Lin MS, Hua CH, Ma WY. Low serum sex hormone-binding globulin: markerofinflammation? Clin Chim Acta. 2012;413:803-807.
36. Yeap BB, Almeida OP, Hyde Z, et al. In men older than 70 years, total testosterone remains stable while free testosterone declines with age. The Health in Men Study. Eur J Endocrinol. 2007;156: 585-594.
37. Kalme T, Koistinen H, Loukovaara M, Koistinen R, Leinonen P. Comparative studies on the regulation of insulin-like growth factor-binding protein-1 (IGFBP-1) and sex hormone-binding globulin (SHBG) production by insulin and insulin-like growth factors in human hepatoma cells. J Steroid Biochem Mole Biol. 2003;86:197-200.
38. Tajar A, Huhtaniemi IT, O'Neill TW, et al. Characteristics of an-drogen deficiency in late-onset hypogonadism: results from the European Male Aging Study (EMAS). J Clin Endocrinol Metab. 2012; 97:1508-1516.
39. Araujo AB, Dixon JM, Suarez EA, Murad MH, Guey LT, Wittert GA. Clinical review: endogenous testosterone and mortality in men: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2011;96:3007-3019.
40. Vikan T, Schirmer H, Njolstad I, Svartberg J. Endogenous sex hormones and the prospective association with cardiovascular disease and mortality in men: the Tromso Study. Eur J Endocrinol. 2009; 161:435-442.
41. Hyde Z, Norman PE, Flicker L, et al. Low free testosterone predicts mortality from cardiovascular disease but not other causes: the Health in Men Study. J Clin Endocrinol Metab. 2012;97:179-189.
42. Pye SR, Huhtaniemi IT, Finn JD, et al. Late-onset hypogonadism and mortality in aging men. J Clin Endocrinol Metab. 2014;99: 1357-1366.
43. Cooper LA, Page ST, Amory JK, Anawalt BD, Matsumoto AM.The associationofobesity with sex hormone-binding globulinisstronger than the association with ageing-implications for the interpretation of total testosterone measurements.Clin Endocrinol. 2015;83:828-833.
44. Vermeulen A, Verdonck G. Representativeness of a single point plasma testosterone level for the long term hormonal milieu in men. J Clin Endocrinol Metab. 1992;74:939-942.