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

Context: During aging, total testosterone (TT) declines and SHBG increases, resulting in a greater decrease in calculated free T (cFT). Currently, guidelines suggest using TT to diagnose androgen deficiency and to reserve cFT only for men with borderline TT. Objective: Our objective was to investigate if either low cFT or low TT is more strongly associated with androgen-related clinical endpoints. Methods: A total of 3334 community-dwelling men, aged 40-79years, were included in this study. Differences in clinical variables between the referent group of men with both normal TT (>= 10.5 nmol/liter) and normal cFT (>= 220 pmol/liter) 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, center, body mass index, and comorbidities. Results: A total of 2641 men had normal TT (18.4 +/- 5.5 [mean +/- SD] nmol/liter)/normal cFT (326 +/- 74 pmol/liter), 277 menhadnorma lTT(14.2 +/- 3.7)/lowcFT(194 +/- 23), 96menhad 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, whereas hemoglobin 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, whereas 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.