Relationships between insulin resistance and frailty with body composition and testosterone in men undergoing androgen deprivation therapy for prostate cancer

Objective: While androgen deprivation therapy (ADT) has been associated with insulin resistance and frailty, controlled prospective studies are lacking. We aimed to examine the relationships between insulin resistance and frailty with body composition and testosterone. Design: Case-control prospective study. Methods: Sixty three men with non-metastatic prostate cancer newly commencing ADT (n = 34) and age-matched prostate cancer controls (n = 29) were recruited. The main outcomes were insulin resistance (HOMA2-IR), Fried's frailty score, body composition by dual x-ray absorptiometry and short physical performance battery (SPPB) measured at 0, 6 and 12 months. A generalised linear model determined the mean adjusted difference (95% CI) between groups. Results: Compared with controls over 12 months, men receiving ADT had reductions in mean total testosterone level (14.1-0.4 nmol/L, P < 0.001), mean adjusted gain in fat mass of 3530 g (2012, 5047), P < 0.02 and loss of lean mass of 1491 g (181, 2801), P < 0.02. Visceral fat was unchanged. HOMA2-IR in the ADT group increased 0.59 (0.24, 0.94), P = 0.02, which was most related to the increase in fat mass (P = 0.003), less to lean mass (P = 0.09) or total testosterone (P = 0.088). Frailty increased with ADT (P < 0.0001), which was related to decreased testosterone (P = 0.028), and less to fat mass (P = 0.056) or lean mass (P = 0.79). SPPB was unchanged. Conclusions: ADT is associated with increased insulin resistance and frailty within 12 months of commencement, independently of confounding effects of cancer or radiotherapy. Insulin resistance appears to be mediated by subcutaneous or peripheral sites of fat deposition. Prevention of fat gain is an important strategy to prevent adverse ADT-associated cardiometabolic risks.