Persisting Muscle Dysfunction in Cushing's Syndrome Despite Biochemical Remission

Frederick Vogel; Leah T. Braun; German Rubinstein; Stephanie Zopp; Heike Künzel; Finn Strasding; Adriana Albani; Anna Riester; Ralf Schmidmaier; Martin Bidlingmaier; Marcus Quinkler; Timo Deutschbein; Felix Beuschlein; Martin Reincke

Disclosures

J Clin Endocrinol Metab. 2020;105(12) 

In This Article

Results

Patient Characteristics

Table 1 shows the clinical and biochemical characteristics of the included patients with CS. Due to pre-existing rheumatic diseases or chronic degenerative arthropathies, 3 and 10 patients, respectively, could not participate in grip strength measurements or CRT. Six months after successful surgery, we observed the expected reduction in BMI (P ≤ 0.001), WHR (P ≤ 0.001 in females, P = 0.008 in males), and HbA1c (P ≤ 0.001; Table 1).

Grip Strength Temporarily Worsens During Steroid Withdrawal and Remains Impaired in Long-term Follow-up

Mean age- and gender-corrected grip strength of the dominant and nondominant hand (mean normalized grip strength) decreased from 83% at diagnosis to 71% 6 months after successful treatment (P ≤ 0.001 vs baseline, Figure 1A and 1B). One year after surgery, mean normalized grip strength had slightly increased to 77% (P = 0.036 vs 6 months) and remained stable at this reduced level without further improvement during follow-up until the end of the observation period at 4 years (P = 0.030 at 4 years follow-up vs controls, Figure 1A).

Figure 1.

A: Age- and gender-corrected grip strength (%) in patients with Cushing's syndrome (CS) at baseline and after successful surgery. Box and whiskers (10th to 90th percentile). Baseline: n = 85; 6 months (mo): n = 69; 1 year (y): n = 55; 2 y: n = 34; 3 y: n = 29; 4 y: n = 22; control: n = 29. Comparisons over time were performed by a Wilcoxon signed rank test and comparisons with control by a Mann-Whitney U test. P < 0.05 was considered statistically significant; * P < 0.05 vs baseline, ** P < 0.05 vs 6-mo follow-up, # P < 0.05 vs control; the higher percentage indicates greater muscle strength. B: Relative changes to baseline in mean normalized grip strength (%) of all patients with CS in remission. Data are given as mean ± SEM.

Chair Rising Test Performance Initially Improves but Remains Impaired During Long-term Follow-up

Patients with CS in remission showed improved CRT performance 6 months after successful surgery compared with baseline (median 8 seconds vs 7 seconds at 6 months follow-up, P = 0.004, Figure 2A and 2B). No further improvement was observed over the next 4 years. Compared with controls, CRT remained abnormal over time (7 seconds in CS at 3 years follow-up vs 5 seconds in controls, P = 0.038, Figure 2A).

Figure 2.

A: Chair rising test performance (seconds) of patients with Cushing's syndrome (CS) at baseline and after successful surgery. Box and whiskers (10th to 90th percentile). Baseline: n = 78; 6 months (mo): n = 64; 1 year (y): n = 50; 2 y: n = 29; 3 y: n = 28; 4 y: n = 21; control: n = 29. Comparisons over time were performed by a Wilcoxon signed rank test and comparisons with control by a Mann-Whitney U test. P < 0.05 was considered statistically significant; * P < 0.05 vs baseline, # P < 0.05 vs control. Shorter time (seconds) indicates greater muscle strength. B: Relative changes to baseline in chair rising test performance (%) of all patients with CS in remission. Data are given as mean ± SEM.

Factors Influencing Long-term Outcome

We identified age, WHR, and HbA1c at the time of diagnosis as associated with the long-term muscle function outcome at 3 years in univariate and multivariate analysis (Table 2 and Table 3 and Supplement Figure 1; all supplementary material and figures are located in a digital research materials repository[17]). Consistent with these findings, a subgroup analysis of patients with pre-existing diabetes mellitus revealed a poorer CRT performance at 3 years (P = 0.009 vs patients without pre-existing diabetes mellitus), whereas Cushing subtype or duration of CS manifestation prior to surgery had no significant influence (Table 2). In a subgroup analysis of 29 patients followed for more than 3 years, patients with long-term glucocorticoid replacement therapy (n = 16) showed similar muscle strength compared with patients without glucocorticoid replacement (n = 13). Urinary free cortisol, late night salivary cortisol, and 1 mg dexamethasone suppression test at diagnosis did not correlate with muscle strength outcomes. Moreover, quality of life, BMI, estimated muscle mass, and body fat percentage at baseline were not associated with muscle strength outcome (Supplement Table 2; all supplementary material and figures are located in a digital research materials repository[17]).

Changes of Body Composition

Anthropometric measurements showed the expected fast decrease in BMI and WHR after successful surgery (Table 1). By performing bioimpedance measurements, body fat percentage and body cell mass (as surrogates for muscle mass) could be estimated. Concerning estimated muscle mass, no relevant differences were observed between baseline and follow-up assessments (Supplement Figure 2; all supplementary material and figures are located in a digital research materials repository[17]). At baseline, estimated muscle mass of 25 kg correlated with bone density (median T-score -1.6, P = 0.017). Body fat percentage decreased from 35% at baseline to 33% at 6 months (P = 0.045) and 29% at 1-year follow-up (P = 0.003, Supplement Figure 2; all supplementary material and figures are located in a digital research materials repository[17]).

Muscle Function is Associated With Quality of Life

Quality of life improved over time according to both the CushingQoL and SF-36 questionnaires (Supplement Table 3; all supplementary material and figures are located in a digital research materials repository[17]). Spearman's correlation analysis showed a strong correlation between muscle function and quality of life during follow-up (Table 4). These data suggest that impaired quality of life not only depends on the severity of muscle dysfunction during hypercortisolism but also on the myopathy outcome in patients with CS in remission.

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