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


J Clin Endocrinol Metab. 2020;105(12) 

In This Article

Patients and Methods


The study was performed as part of the German Cushing's Registry, a multicenter longitudinal cohort study, which has enrolled a total of 317 patients in 6 centers since 2012. For the current prospective study, we selected 88 patients with endogenous CS and consecutive muscle function tests diagnosed between 2012 and 2018 at 3 sites of the German Cushing's Registry (Ludwig Maximilians University Munich, n = 66; University Hospital Würzburg, n = 18; Endocrinology outpatient clinic in Charlottenburg, Berlin, n = 4). All patients had typical signs and symptoms of CS. The diagnosis and subtype differentiation of CS were done as reported earlier according to current guidelines and recommendations.[14,16] All 88 patients (49 with Cushing's disease, 34 patients with cortisol-producing adrenal adenoma, and 5 patients with ectopic CS) were followed-up prospectively. Patients with subclinical hypercortisolism, adrenocortical cancer, and adrenostatic or radiotherapeutic therapy were excluded. All 88 patients underwent successful surgery, leading to sustained biochemical remission. In 9 cases with pituitary CS, a second surgery was necessary to achieve remission. Median time to remission from diagnosis was 2 months, and median time to remission from the first symptoms was 25 months. Due to pre-existing rheumatic disorders or degenerative joint diseases (ie, coxarthrosis), 13 patients could not perform either grip strength or the chair rising test (CRT). Out of all 88 patients included with baseline muscle function examination, grip strength data was available from 85 patients and CRT data from 78 patients. Patients were re-examined clinically and biochemically in regular follow-up visits 6 and 12 months after final surgery, and afterwards annually. Due to a shorter remission time of recently included patients, the number of patients decreases with time (6 months: n = 69; 1 year: n = 55; 2 years: n = 34; 3 years: n = 29; 4 years: n = 22). The mean follow-up for all patients with CS was 2.2 years. Only patients with at least 1 follow-up visit in addition to baseline visit were included in the study. For the comparison of muscle function, we recruited a control group of rule-out CS patients who had no biochemical evidence of CS. The control group (n = 29) was matched according to body mass index (BMI), age, and gender of patients with CS who have been in remission for 3 years (n = 29; Supplement Table 1; all supplementary material and figures are located in a digital research materials repository[17]). All patients and controls gave written, informed consent. The protocol was approved by the ethics committee of the participating centers.

Muscle Strength Measurements

Hand grip strength was measured 3 times on both hands per visit in a sitting position. The measurements were performed in a standardized manner with the JAMAR hydraulic hand dynamometer (Patterson Medical, Nottinghamshire, UK). The mean grip strengths (kg) for the dominant and nondominant hand were calculated out of 3 repetitions. The hand with the better performance at baseline was defined as the dominant hand. To adjust for age and gender, grip strength was standardized (normalized grip strength) to the manufacturer's information on normative grip strength data.[18,19] Mean normalized grip strength was determined from the mean value of dominant and nondominant grip strength according to age and gender. To determine muscle function of the lower limbs, CRT was performed, as previously described in other studies.[14,20] The test was conducted by rising up from a sitting position 5 times as fast as possible. The patients kept their arms crossed over their chest while performing the exercise. The time (seconds) needed for the procedure (with ending in a standing position) was recorded and compared.

Bioimpedance Measurements and Biometrics

By using a bioimpedance measuring device at 50 kHz with 400 μA by Data Input (Poecking, Germany), body cell mass and body fat percentage was estimated according to the manufacturer's information. Two pairs of current-introducing and voltage-sensing electrodes were attached to the dorsum of a hand and a foot. All impedance measurements were taken after fasting, the arms relaxed at the sides without touching the body. Bioimpedance and anthropometric measurements such as BMI and waist-to-hip ratio (WHR) were performed by the same skilled investigator in a standardized manner.

Quality of Life

To analyze quality of life in patients with CS, 2 inventories were used: the disease-specific questionnaire, Cushing's quality of life (CushingQoL),[21] and the Short Form 36 health survey (SF-36).[22] The SF-36 Physical Component Summary and SF-36 Mental Component Summary were gained by weighting and summing up the original scales of the SF-36 according to Ellert et al,[23] and in relation to a German normative population.[24]

Laboratory Analysis

In all patients, blood samples were taken in a fasting state at time of diagnosis, 6 months after successful surgery and in line with the follow-up visits once a year. The analyses were performed in the central laboratories of the involved centers using standard methods.

Statistical Evaluation

Statistical analysis was performed using SPSS (version 25). Patient characteristics are shown as median and 25th and 75th percentiles in brackets. For comparison between different time points, the Wilcoxon signed rank test was used. Differences between the groups were analyzed using the Mann-Whitney U test and Kruskal–Wallis test. Based on a difference of 23% in normalized grip strength and 2 seconds in CRT after 3 years, a power of 0.8 and P-level of 0.05, the study required the participation of a minimum of 18 patients per group. Because of the decreasing number (<20) of patients with CS after 5 years, we limited the observation period to 4 years. To identify independent variables influencing muscle strength, outcome correlations between muscle strength and clinical parameters were determined using the Spearman's rank correlation coefficient. Multiple linear regression analysis was performed with the variables of age, WHR, and hemoglobin A1c (HbA1c). P-values of <0.05 were considered to indicate statistical significance.