Impaired Muscle Strength and Performance in Patients With Mild Autonomous Cortisol Secretion

Background: Glucocorticoid-induced myopathy is well-recognized in overt Cushing syndrome (CS), but the impact of mild cortisol secretion on muscle is unclear. Recent data suggest that patients with mild autonomous cortisol secretion (MACS) are frailer and report more weakness than patients with non-functioning adrenal adenomas. We hypothesized that MACS is associated with 1) objective measures of impaired muscle strength and performance and 2) increased tissue accumulation of advanced glycation end products (AGEs), a measure of accelerated aging. Aim: To determine the effect of MACS on muscle mass, strength, performance, and tissue accumulation of AGEs. Methods: We conducted a cross-sectional analysis as part of an ongoing cohort study in patients with MACS compared to age and sex-matched referent subjects without cortisol excess. MACS was defined as serum cortisol >1.8 mcg/dL after the 1 mg overnight dexamethasone suppression test (DST), in the absence of overt signs and symptoms of CS. We measured hand grip strength with hand grip dynamometer and evaluated functional performance on the timed up and go test, 6 minute walk test, and gait speed assessment. Tissue accumulation of AGEs was measured with point-of-care AGE reader. Appendicular lean mass was calculated and adjusted for height in participants who underwent body composition scan. Results: A total of 23 patients with MACS and 23 age and sex-matched referent subjects without cortisol excess were enrolled. The median age of diagnosis was 63 years (range, 51–81), and 26 (56%) were women. In the MACS cohort, median cortisol following 1 mg DST was 2.6 µg/dL (range, 1.9–13.0), median DHEA-S 37 µg/dL (range, 5.0- 141.0), and median ACTH 8.5 pg/mL (range, 5.0–38.0). Patients with MACS had lower hand grip strength (median 29.3 vs. 32.5 kg, p=0.052), slower gait speed (median 1.1 vs. 1.4 m/s, p=0.001), covered less distance during the 6 minute walk test (median 453 vs. 510 m, p=0.001), and took longer to complete the timed up and go test (median 10.1 vs. 8.6 s, p=0.04) than referent subjects without cortisol excess. Accumulation of AGEs was higher in patients with MACS (median 2.9 vs. 2.4, p=0.01). No significant difference was observed in appendicular lean mass (n=19 pairs, 7.8 vs. 7.5 kg/m2, p=0.57). Conclusions: MACS is associated with decreased muscle strength and performance without a significant change in muscle mass, suggesting poor muscle quality. We also observed increased tissue accumulation of AGEs in MACS patients, consistent with our hypothesis of MACS-induced accelerated aging. These findings may help explain the increased frailty observed in MACS, and suggest muscle assessment be considered in all patients with autonomous cortisol secretion. Further studies should examine the impact of muscle and functional impairments on morbidity in MACS, and its possible reversal with either a structured exercise intervention or adrenalectomy.