Low Free Testosterone is Associated with Hypogonadal Signs and Symptoms in Men with Normal Total Testosterone

CONTEXT - During ageing, total testosterone (TT) declines and SHBG increases, resulting in a greater decrease in calculated free testosterone (cFT). Currently, guidelines suggest using TT to diagnose androgen deficiency and to reserve cFT only for men with borderline TT.

OBJECTIVE - To investigate if either low cFT or low TT is more strongly associated with androgen-related clinical endpoints.

METHODS - 3334 community-dwelling men, aged 40-79, were included. Differences in clinical variables between the referent group of men with both normal TT (≥10.5 nmol/L) and normal cFT (≥220 pmol/L) with those who had normal TT/low cFT, low TT/normal cFT and low TT/low cFT, were assessed by regression models adjusted for age, centre, BMI and comorbidities.

RESULTS - 2641 men had normal TT [18.4±5.5 (mean±SD) nmol/L]/normal cFT (326±74 pmol/L), 277 men had normal TT (14.2±3.7)/low cFT (194±23), 96 men had low TT (9.6±0.7)/normal cFT (247±20) and 320 men had low TT (7.8±2.5)/low cFT (160±55). Men with normal TT/low cFT were older and in poorer health. They had higher SHBG and LH, and reported more sexual and physical symptoms, while haemoglobin and bone ultrasound parameters were lower compared to the referent group. Men with low TT/normal cFT were younger and more obese. They had lower SHBG, but LH was normal, while features of androgen deficiency were lacking.

CONCLUSIONS - Low cFT, even in the presence of normal TT, is associated with androgen deficiency-related symptoms. Normal cFT, despite low TT, is not associated with cognate symptoms. Therefore cFT levels should be assessed in men with suspected hypogonadal symptoms.

The Journal of clinical endocrinology and metabolism. 2016 Feb 24 [Epub ahead of print]

Leen Antonio, Frederick C W Wu, Terence W O'Neill, Stephen R Pye, Tomas B Ahern, Michaël R Laurent, Ilpo T Huhtaniemi, Michael E J Lean, Brian G Keevil, Giulia Rastrelli, Gianni Forti, György Bartfai, Felipe F Casanueva, Krzysztof Kula, Margus Punab, Aleksander Giwercman, Frank Claessens, Brigitte Decallonne, Dirk Vanderschueren, EMAS Study Groupdagger

Department of Clinical and Experimental Medicine, KU Leuven, Laboratory of Clinical and Experimental Endocrinology, Leuven, Belgium;, Andrology Research Unit, Endocrinology and Diabetes Research Group, Institute of Human Development, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, UK;, Arthritis Research UK Centre of Epidemiology, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK;, Arthritis Research UK Centre of Epidemiology, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK;, Andrology Research Unit, Endocrinology and Diabetes Research Group, Institute of Human Development, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, UK;, Department of Cellular and Molecular Medicine, KU Leuven, Laboratory of Molecular Endocrinology, Leuven, Belgium;, Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, London, UK and Department of Physiology, Institute of Biomedicine, University of Turku, Finland;, Department of Human Nutrition, University of Glasgow, Glasgow, UK;, Department of Clinical Biochemistry, University Hospital of S Manchester, Manchester, UK;, Sexual Medicine and Andrology Unit, Department Of Experimental Clinical And Biochemical Sciences, University of Florence, Florence, Italy;, Endocrinology Unit, Department Of Experimental Clinical And Biochemical Sciences, University of Florence, Florence, Italy;, Department of Obstetrics, Gynaecology and Andrology, Albert Szent-György Medical University, Szeged, Hungary;, Department of Medicine, Santiago de Compostela University, Complejo Hospitalario Universitario de Santiago (CHUS); CIBER de Fisiopatología Obesidad y Nutricion (CB06/03), Instituto Salud Carlos III; Santiago de Compostela, Spain;, Department of Andrology and Reproductive Endocrinology, Medical University of Łódź, Łódź, Poland;, Andrology Unit, United Laboratories of Tartu University Clinics, Tartu, Estonia;, Reproductive Medicine Centre, Skåne University Hospital, University of Lund, Sweden., Department of Cellular and Molecular Medicine, KU Leuven, Laboratory of Molecular Endocrinology, Leuven, Belgium;, Department of Clinical and Experimental Medicine, KU Leuven, Laboratory of Clinical and Experimental Endocrinology, Leuven, Belgium;, Department of Clinical and Experimental Medicine, KU Leuven, Laboratory of Clinical and Experimental Endocrinology, Leuven, Belgium;

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