Abstract
Objective
Prospective data on determinants of muscle strength impairment and quality of life in patients with various subtypes and severity of endogenous hypercortisolism are lacking.
Design
Single-center cross-sectional study, 2019 to 2022.
Methods
Patients with Cushing syndrome (CS) and mild autonomous cortisol secretion (MACS) were assessed with clinical and biochemical severity scores, muscle function (nondominant hand grip strength and sit-to-stand test), and quality of life (Short Form-36 [SF36] and CushingQoL). Referent subjects were recruited from the local population undergoing abdominal imaging for reasons other than suspected adrenal disorder.
Results
Of 164 patients, 81 (49%) had MACS, 14 (9%) had adrenal CS, 60 (37%) had pituitary CS, and 9 (5%) had ectopic CS. Median age was 53 years (interquartile range: 42-63 years), and 126 (77%) were women. The SF36 mental component score was similarly low in patients with MACS vs CS, but physical component score was lower in CS when compared to MACS (mean of 34.0 vs 40.5, P = .001). Compared to MACS, patients with CS had lower scores on the standardized CushingQoL (mean of 47.1 vs 34.2, P < .001). Compared to referent subjects, patients with MACS demonstrated reduced muscle strength, similar to patients with CS (mean sit to stand Z-score of −0.47 vs −0.54, P = .822). Clinical severity (r = −0.22, P = .004) but not biochemical severity was associated with sit-to-stand test performance.
Conclusions
Both patients with overt CS and MACS demonstrate reduced muscle strength and low quality of life. The clinical severity score utilized is associated with both physical and psychosocial components of CushingQoL and with the physical component of SF36.
Keywords: Cushing syndrome, mild autonomous cortisol secretion, MACS, chair rising, sit to stand
Significance.
In this study of patients with Cushing syndrome (CS) and mild autonomous cortisol secretion (MACS), we developed and characterized patients using clinical and biochemical severity scoring systems, assessed quality of life and muscle strength using both hand grip strength and sit-to-stand test. Notably, we found no differences in the degree of muscle function impairment between patients with MACS and those with CS. We showed the association of clinical severity score, but not biochemical severity score, with the quality of life, as well as muscle strength impairment. The clinical severity score may simplify the initial assessment and potentially guide the management of patients with MACS.
Introduction
Cushing syndrome (CS) is a rare and challenging endocrine disorder caused by chronic cortisol excess.1 Endogenous CS has an estimated incidence of around 2.5 cases per million per year.2,3 Mild autonomous cortisol secretion (MACS) from adrenal adenomas or hyperplasia is more common, affecting up to 50% of patients with adrenal adenomas (1%-2% of general population).4-7 Patients present with a variable degree of hypercortisolism, ranging from subtle hormonal alterations of the hypothalamic-pituitary-adrenal axis in the absence of clinical symptoms or signs (as in MACS), to overt CS, when patients develop overt physical features in addition to metabolic derangements, and demonstrate high mortality.1,8
Previous studies demonstrated several factors associated with impaired quality of life in patients with untreated CS, including age, sex, severity of hypercortisolism, delayed diagnosis, CS subtype, and availability of support systems.9-14 However, classification of biochemical and/or clinical severity of cortisol excess was usually based on a single or a combination of standard of care tests or a binary classification of presence/absence of overt CS features, which do not allow for detailed characterization of the degree of hypercortisolism severity. In addition, these studies were mostly retrospectively designed, used heterogeneous diagnostic criteria, and did not include patients with milder forms of cortisol excess.9-14
Furthermore, although proximal muscle weakness is one of the most common symptoms of CS and often the most debilitating,1 it has been rarely evaluated using objective measures in previous studies. Two studies from the German Cushing's Registry reported lower hand grip strength and sit-to-stand test performance in patients with CS compared to referent subjects,15,16 however, these studies did not include patients with MACS. Most current data in patients with CS originates from Europe9-16 with no large cross-sectional studies originating from North America.
Here, we utilize an ongoing longitudinal prospective study of patients with endogenous hypercortisolism and apply clinical and biochemical severity scoring systems to determine the association of the hypercortisolism severity with quality of life and muscle strength outcomes in both patients with MACS and CS.
Methods
Participants
This research complied with the Declaration of Helsinki. After obtaining approvals from the Mayo Clinic Institutional Review Board (Rochester, MN, United States) in August 2019, patients with all types of endogenous hypercortisolism (pituitary CS, adrenal CS, ectopic CS, and MACS from adrenal adenomas or hyperplasia) were consecutively screened, consented, and enrolled from the Pituitary-Adrenal Clinic at Mayo Clinic in Rochester, MN. Inclusion criteria were: (1) adults with endogenous CS or MACS referred for surgery and (2) absence of exogenous glucocorticoid exposure. The diagnosis of CS was made using Endocrine Society guidelines with at least 2 positive results of the following 3 case detection tests—morning cortisol after 1 mg overnight dexamethasone suppression test, late-night salivary cortisol, and 24-hour urinary free cortisol.17 The MACS was diagnosed using the guidelines from the European Network for the Study of Adrenal Tumors (ENSAT)—if abnormal morning serum cortisol >1.8 μg/dL after overnight 1 mg dexamethasone suppression test, without overt features of hypercortisolism.5 Medical records were reviewed for demographic information, past medical history, medications, and hormonal workup. Study investigators conducted a 60-to-120-minute study interview with each participant to review symptomatology related to hypercortisolism using a standardized assessment, perform a focused physical examination, confirm medical comorbidities and current medications, measure muscle strength, and administer the quality-of-life questionnaires. All data were entered into the Research Electronic Data Capture for storage.18
In a parallel study approved by the Institutional Review Board, referent subjects were recruited from the local population of patients referred for the abdominal computed tomography scan for reasons other than known or suspected adrenal disorder (to avoid possible imaging bias). The absence of features suggestive of CS was further excluded by the physical exam. Subjects were excluded if exposed to exogenous glucocorticoids within the 3 months prior to participation or if they had history of long-standing glucocorticoid use prior to enrollment. Referent subjects were age, sex, and body mass index (BMI)-matched to patients with MACS. All referent subjects underwent a clinical interview and a focused physical exam, completed a SF36 questionnaire, and had a nondominant hand grip measured.
Classification of severity of cortisol excess
To characterize the full spectrum of patients presenting with endogenous hypercortisolism, we developed separate clinical and biochemical scoring systems to grade severity based on Endocrine Society guidelines on the diagnosis of CS,17 ENSAT guidelines on adrenal incidentalomas,5 recent systematic review on MACS,19 and expert opinion (W.F.Y. and I.B.), Appendix Tables 1 and 2.
Clinical severity
Clinical severity was assessed by evaluating for presence of metabolic and/or physical findings related to cortisol excess (Appendix Table 1). Metabolic abnormalities assessed included: Hypertension, abnormal glucose metabolism (prediabetes or type 2 diabetes mellitus), decreased bone density (osteopenia, osteoporosis with or without fragility fractures in the past 12 months), and venous thromboembolic events in the past 12 months. Physical examination findings assessed included: Central obesity, presence of supraclavicular and/or dorsocervical fat pads, rounding of the face with or without plethora, skin changes (acne, violaceous striae, thinning, and/or bruising of the skin), and subjective complaint of proximal muscle weakness.
Biochemical severity
Biochemical severity assessment included evaluation of hormonal abnormalities diagnostic of hypercortisolism (the 24-hour urinary free cortisol, morning serum cortisol after 1-mg dexamethasone overnight administration, and late-night salivary cortisol), and degree of ACTH-independence in patients with adrenal CS or MACS (baseline ACTH and age/sex-adjusted cutoff for dehydroepiandrosterone sulfate [DHEA-S]). As patients may not have completed all available diagnostic tests, we used the sum of the 2 most abnormal tests to calculate the final biochemical severity score (Appendix Table 2).
Muscle function assessment
Hand grip strength test
Hand grip strength was measured with a Jamar Plus+ digital hand dynamometer (Sammons Preston, Bolingbrook, IL, United States), according to the Southampton Grip-Strength Measurement Protocol.20 The self-identified nondominant hand was tested in ambidextrous individuals. The dynamometer handle was set in the second smallest position, unless deemed uncomfortable by the participant. For testing, the participant sat upright in a chair with feet flat on the floor, elbow at 90 degrees of flexion, and forearm on the arm rest of the chair. The wrist was over the end of the arm rest with forearm in mid-pronation/supination, so the dynamometer was unsupported and held vertical. The participant was instructed to squeeze as hard as they could for a minimum of 3 seconds keeping their trunk and arm stationary. The peak reading was recorded, and the test repeated twice more with 30-second intervening rest periods. The maximum nondominant hand grip strength recorded from the 3 trials was used in analyses.
Sit-to-stand test
Sit-to-stand test performance was assessed during a single 30-second test using a standard protocol.21 Each test was performed in shoes and with a standardized chair (seat height = 45 cm). After the participant completed a satisfactory initial single sit-to-stand maneuver with their arms folded across their chest, the tester started a countdown timer set to 30 seconds. The tester counted aloud with a consistent tone and volume each time the participant stood up until the 30-second countdown timer expired. No additional motivational input was provided. If a halfway standing position was reached when time elapsed, it was counted as a stand.
Health-related quality of life assessment
After the diagnosis of hypercortisolism was confirmed and prior to any treatment or surgery, each study participant completed 2 sets of questionnaires: The Short Form-36 (SF36) as the general health-related quality-of-life questionnaire and the CushingQoL as the disease-specific health-related quality-of-life questionnaire.
Short Form-36
The SF36 is a self-assessment of quality of life over the preceding 4 weeks in 8 domains of health: Physical functioning (PF), role-physical limitation (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role-emotional limitation (RE), and mental health (MH). In each domain, the range is from 0 to 100, with higher scores indicating less pain or better functioning.22 The PF, RP, BP, and GH were merged into a comprehensive index for PF (physical component summary [PCS]) while VT, SF, RE, and MH were merged into a comprehensive index of mental functioning (mental component summary [MCS]).23,24 The SF36 components and component summaries were standardized using age and sex-specific reference values for the US adult population and scaled to have a mean of 50 and standard deviation of 10; higher scores indicate better health states. The SF36 scores within 5 points of the norm (45 to 55) are generally considered to be average or normative, whereas scores more than 10 points below the norm (<40) are indicative of significantly impaired health.23,24
CushingQoL questionnaires
The CushingQoL is a validated disease-specific questionnaire consisting of 12 questions on a 5-point Likert scale ranging from always to never (for 10 questions) or very much to not at all (for 2 questions).14 The total score ranges from 12 to 60, with a lower score indicating greater negative impact on health-related quality of life. The score is standardized and converted to a 0-100 scale with 0 indicating the worst quality of life and 100 indicating the best quality of life. Due to rarity of CS, normative data on age and sex-specific values are not yet available. CushingQoL has been demonstrated to be feasible, reliable, valid, and correlate well with SF36 in clinical practice.14
Statistical analysis
Continuous lab measurements and baseline patient characteristic variables were reported as median and interquartile range (IQR). Normative data of US population in hand grip strength, sit-to-stand test, and SF36 were used to convert the respective results into age- and sex-adjusted normative scores, as well as to calculate PCS and MCS scores of SF3621,23 and were reported using means and standard deviations, and comparisons were made with 2-sample t-tests. For all other continuous variables, comparisons were performed using a Kruskal-Wallis test, and for categorical variables, comparisons were made with the chi-squared test. Partial Pearson correlation coefficients, adjusting for age and sex, were used to assess the relationship between various measurements. Multivariable analysis was performed using linear regression analysis to better understand the relationship of adjustment variables with key study endpoints. A 2-tailed probability value of P < .05 was considered statistically significant for all tests. Statistical analysis was conducted using R, version 4.2.2.
Results
Patient characteristics
Of 164 patients included in the analyses, 81 (49%) had MACS, 14 (9%) had adrenal CS, 60 (37%) had pituitary CS, and 9 (5%) had ectopic CS. Median age at the time of enrollment was 53 years (IQR: 42-63 years), 126 (77%) were women, and 151 (92%) were Caucasian. The median duration of CS symptoms prior to diagnosis was 12 months (IQR: 4-36 months) and were longest in patients with pituitary CS (33 months, vs 12 months in adrenal CS, vs 4 months in ectopic CS), Appendix Table 3. When compared to patients with CS, patients with MACS were older and had lower BMI, Table 1. As expected, patients with CS had a higher prevalence of physical exam features such as weight gain, truncal obesity, supraclavicular and/or dorsocervical fat accumulation, facial rounding and plethora, striae, thinning or bruising, and self-reported muscle weakness, Table 1.
Table 1.
Participant characteristics.
| Variables | n available | Mild autonomous cortisol secretion (n = 81) |
Overt Cushing syndrome (n = 83) |
P-value |
|---|---|---|---|---|
| Women, n (%) | 164 | 59 (73) | 67 (81) | .232 |
| Caucasian, n (%) | 164 | 76 (94) | 75 (90) | .411 |
| Age at enrollment, years Median (IQR) |
164 | 57 (49-64) |
48 (39-61) |
<.001 |
| Clinical assessment and physical exam findings | ||||
| BMI, kg/m2 Median (IQR) |
164 | 30.9 (27.0-37.9) |
35.0 (30.3-42.9) |
.004 |
| Duration of symptoms before diagnosis, months Median (IQR) |
164 | — | 24 (11-51) |
|
| Hypertension, n (%) Treatment with ≥3 anti-hypertensives, n (%) |
164 | 65 (80) 23 (28) |
70 (84) 26 (31) |
.492 .683 |
| Hyperglycemia, n (%) | 164 | |||
| Prediabetes | 26 (32) | 26 (31) | .525 | |
| Type 2 diabetes mellitus | 25 (31) | 32 (39) | ||
| Treatment with insulin | 12 (15) | 15 (18) | .574 | |
| Decreased bone density, n (%) | 164 | |||
| Osteopenia | 22 (27) | 31 (37) | .375 | |
| Osteoporosis | 13 (16) | 12 (14) | ||
| Fragility fracture within past 12 months, n (%) | 164 | 2 (2) | 10 (12) | .019 |
| Hyperlipidemia, n (%) | 156 | 55 (68) | 54 (72) | .577 |
| Atherosclerotic cardiovascular disease, n (%) | 164 | 11 (14) | 4 (5) | .052 |
| Venous thromboembolic event in past 12 months, n (%) | 164 | 1 (1) | 5 (6) | .102 |
| Weight gain, n (%) | 164 | 42 (52) | 77 (93) | <.001 |
| Truncal obesity, n (%) | 164 | 31 (38) | 75 (90) | <.001 |
| Supraclavicular and/or dorsocervical fat accumulation, n (%) | 164 | 22 (27) | 68 (82) | <.001 |
| Rounding of the face ± plethora, n (%) | 164 | 17 (21) | 73 (88) | <.001 |
| Skin changes (violaceous striae, thinning, and/or bruising), n (%) | 164 | 25 (31) | 65 (78) | <.001 |
| Proximal muscle weakness (self-reported), n (%) | 164 | 39 (48) | 56 (67) | .012 |
| Clinical severity score Median (IQR) |
164 | 7 (3-10) |
15 (11-18) |
<.001 |
| Biochemical assessment a | ||||
| 1-mg DST, μg/dL Median (IQR) |
131 | 3.4 (2.6-5.7) |
11.2 (5.4-15.2) |
<.001 |
| 8-mg DST, μg/dL Median (IQR) |
33 | 2.4 (1.8-3.3) |
2.8 (2.4-4.2) |
.277 |
| 24-Hour urine cortisol, μg/24 hours Median (IQR) |
115 | 25.0 (16.3-42.8) | 141 (68.0-353.0) | <.001 |
| Late-night salivary cortisol, ng/dL Median (IQR) |
76 | 69 (50-160) |
248 (160-430) |
.002 |
| Baseline morning ACTH, pg/mL Median (IQR) |
161 | 8.1 (5.7-12.9) |
ACTH-dependent: 75.0 (48.8-108.2) ACTH-independent: 4.9 (4.9-4.9) |
<.001 |
| Baseline DHEA-S, μg/dL Median (IQR) |
159 | 37.0 (22.5-57.5) |
ACTH-dependent: 149.0 (92.8-226.2) ACTH-independent 40.0 (16.0-63.0) |
<.001 |
| Biochemical severity score Median (IQR) |
164 | 3 (2-4) |
7 (6-8) |
<.001 |
Reference ranges are provided in Appendix Table 2.
Abbreviations: ACTH, adrenocorticotrophic hormone; BMI, body mass index; DHEA-S, dehydroepiandrosterone sulfate; DST, dexamethasone suppression test; IQR, interquartile range.
Prevalence of comorbidities were similar in patients with CS and MACS, except for a higher prevalence of fragility fractures in patients with CS (12% vs 2% in MACS, P = .019), Table 1. Compared to sex, age, and BMI-matched referent subjects, patients with MACS had higher prevalence of hypertension, dysglycemia, low bone mass, and dyslipidemia, Table 2. In addition, prevalence of hypertension treated with at least ≥3 anti-hypertensive medications (28% vs 2%, P < .001) and insulin dependent diabetes mellitus type 2 (15% vs 1%, P < .001) were much higher in patients with MACS, Table 2.
Table 2.
Differences between patients with mild autonomous cortisol secretion and referent subjects.
| Variables | Mild autonomous cortisol secretion (n = 81) |
Referent subjects (n = 81) |
P-value |
|---|---|---|---|
| Women, n (%) | 59 (73) | 59 (73) | — |
| Caucasian, n (%) | 76 (94) | 73 (90) | .386 |
| Age at enrollment, years Median (IQR) |
57 (49-64) | 56 (50-66) | .736 |
| BMI, kg/m2 Median (IQR) |
30.9 | 30.4 | .184 |
| (27.0-37.9) | (26.2-33.5) | ||
| Hypertension, n (%) | 65 (80) | 28 (35) | <.001 |
| Treatment with ≥3 anti-hypertensives, n (%) | 23 (28) | 2 (2) | <.001 |
| Hyperglycemia, n (%) | |||
| Prediabetes | 26 (32) | 13 (16) | <.001 |
| Type 2 diabetes mellitus | 25 (31) | 9 (11) | |
| Treatment with insulin | 12 (15) | 1 (1) | .001 |
| Decreased bone density, n (%) | |||
| Osteopenia | 22 (27) | 1 (1) | |
| Osteoporosis | 13 (16) | 2 (3) | <.001 |
| Fragility fracture within past 12 months, n (%) | 2 (2) | 0 (0) | .155 |
| Hyperlipidemia, n (%) | 55 (68) | 42 (52) | .037 |
| Atherosclerotic cardiovascular disease, n (%) | 11 (14) | 7 (9%) | .317 |
| Venous thromboembolic event in past 12 months, n (%) | 1 (1) | 2 (2) | .560 |
Abbreviations: BMI, body mass index; IQR, interquartile range.
Biochemical and clinical severity scores
Patients with CS had a higher clinical severity score (median of 15 vs 7, P < .001) and higher biochemical severity score (median of 7 vs 4, P < .001), Table 1. Among the 4 subtypes of hypercortisolism, patients with ectopic CS had the highest clinical score (median: 17, IQR: 16-19) and biochemical severity score (median: 9, IQR: 7-11) and patients with MACS had the lowest clinical score (median: 7, IQR: 3-10) and biochemical score (median: 3, IQR: 2-4), while patients with pituitary CS and adrenal CS had similar biochemical and clinical severity scores, Appendix Table 3, Figure 1A, B. Overall, there was good correlation between the clinical and biochemical severity scores (r = 0.46, P < .001, Figure 1C).
Figure 1.
(A) Clinical severity score in different subtypes of Cushing syndrome. (B) Biochemical severity score in different subtypes of Cushing syndrome. (C) Correlation between the clinical and biochemical severity scores. Abbreviation: MACS, mild autonomous cortisol secretion.
Muscle strength measures
Patients with CS and MACS had similarly impaired muscle strength when measured by assessments of the nondominant hand grip strength and sit-to-stand test performance, Table 3. In comparison to referent subjects, patients with MACS had lower nondominant hand grip strength (mean Z-score of −0.16 vs 0.51, P = .001), Table 3.
Table 3.
Muscle strength and quality of life assessment in patients with hypercortisolism and referent subjects.
| Referent subjects (n = 81) |
Mild autonomous cortisol secretion (n = 81) |
Overt Cushing syndrome (n = 83) |
MACS vs CS (P-value) |
MACS vs referent subjects (P-value) |
|
|---|---|---|---|---|---|
| Muscle strength (Z-score, mean ± standard deviation) | |||||
| Nondominant hand grip | 0.51 ± 0.88 | −0.02 ± 1.07 | −0.16 ± 1.02 | .411 | .001 |
| Sit-to-stand test | — | −0.47 ± 1.53 | −0.54 ± 2.10 | .822 | |
| Short Form-36 questionnaire (age- and sex-adjusted sub-scores, mean ± standard deviation) | |||||
| Physical functioning | 55.60 ± 5.28 | 40.48 ± 14.17 | 32.83 ± 13.83 | .001 | <.001 |
| Role-physical limitation | 55.02 ± 5.18 | 38.86 ± 11.83 | 32.60 ± 12.07 | .001 | <.001 |
| Body pain | 55.24 ± 6.61 | 45.15 ± 10.67 | 42.88 ± 12.23 | .214 | <.001 |
| General health | 54.14 ± 7.22 | 39.76 ± 10.57 | 34.50 ± 11.65 | .003 | <.001 |
| Social functioning | 55.32 ± 5.91 | 40.40 ± 12.71 | 33.96 ± 12.76 | .002 | <.001 |
| Role-emotional limitation | 54.76 ± 4.51 | 41.03 ± 12.38 | 37.77 ± 13.29 | .111 | <.001 |
| Vitality | 54.09 ± 8.84 | 37.22 ± 11.01 | 33.35 ± 8.75 | .015 | <.001 |
| Mental health | 55.19 ± 7.30 | 41.94 ± 10.74 | 40.45 ± 12.21 | .417 | <.001 |
| Short Form-36 questionnaire (age- and sex-adjusted composite scores, mean ± standard deviation) | |||||
| Physical component summary | 54.95 ± 6.41 | 40.52 ± 11.77 | 34.05 ± 12.68 | .001 | <.001 |
| Mental component summary | 54.67 ± 7.14 | 40.17 ± 11.87 | 38.10 ± 12.55 | .289 | <.001 |
| CushingQoL questionnaire (mean ± standard deviation) | |||||
| Standardized psychosocial QoL | — | 47.55 ± 21.69 | 36.14 ± 19.89 | .001 | — |
| Standardized physical QoL | — | 45.25 ± 23.93 | 27.98 ± 21.18 | <.001 | — |
| Standardized overall QoL | — | 47.13 ± 20.39 | 34.18 ± 18.44 | <.001 | — |
Abbreviations: CS, Cushing syndrome; MACS, mild autonomous cortisol secretion; QoL, quality of life.
When examining CS subtypes, no differences in muscle strength were found between groups, Appendix Table 4. While sit-to-stand test performance correlated with the nondominant hand grip results (sex- and age-adjusted r = 0.31, P < .001) (Figure 2), assessment of muscle strength using the sit-to-stand test was more impaired in both patients with MACS and CS than the hand grip strength, Table 3, Appendix Table 4.
Figure 2.
Age- and sex-adjusted Pearson correlation coefficients between various parameters. Abbreviations: BMI, body mass index; CSQoL, CushingQoL; MCS, mental component summary; PCS, physical component summary; SF36, Short Form-36. Footnote: See Appendix Table 5 for the number of observations available for each correlation (154-164).
In the sex- and age-adjusted analysis, clinical severity (r = −0.24, P = .004) but not biochemical severity was associated with sit-to-stand test results, and no association was found with the nondominant hand grip strength with either clinical or biochemical severity (Appendix Table 5, Figures 2 and 3).
Figure 3.
(A) Association between clinical severity score and sit-to-stand test. (B) Association between clinical severity score and nondominant hand grip strength. (C) Association between biochemical severity score and sit-to-stand test. (D) Association between biochemical severity score and nondominant hand grip strength. Abbreviation: MACS, mild autonomous cortisol secretion. Footnote: 159 observations are available.
Quality-of-life measures
In all patients with hypercortisolism including MACS, mean Z-scores in the 8 dimensions of SF36 were universally below 50, demonstrating a lower self-perceived quality of life in patients with hypercortisolism when compared to their sex- and age-matched general population. Clinical severity but not biochemical severity score was associated with quality-of-life measures, Figure 4. On SF36, the PCS score was lower in the patients with CS when compared to patients with MACS (34.05 ± 12.68 vs 40.52 ± 11.77, P = .001) but the MCS scores were not significantly different between the 2 groups, Table 3. Similarly, CushingQoL score was also higher in patients with MACS vs patients with CS, Table 3. In sex- and age-adjusted analysis, clinical severity was associated with SF36 PCS (r = −0.43, P < .001), as well as CushingQoL total (r = −0.37, P < .001), psychosocial (r = −0.30, P < .001), and physical scores (r = −0.39, P < .001), Appendix Table 4, Figure 2. Biochemical severity score was not associated with the quality of life except for physical component of the CushingQoL (r = −0.29, P < .001), Appendix Table 4, Figure 2. In a multivariable analysis of age, sex, BMI, and clinical severity, we found that the clinical severity score was associated with the physical component of SF36 as well as with total and both physical and psychosocial subcomponents of the CushingQoL, Table 4.
Figure 4.
(A) Association between clinical severity score and physical component summary score of Short Form-36. (B) Association between biochemical severity score and physical component summary score of Short Form-36. (C) Association between clinical severity score and mental component summary score of Short Form-36. (D) Association between biochemical severity score and mental component summary score of Short Form-36. (E) Association between clinical severity score and standardized CushingQoL score. (F) Association between biochemical severity score and standardized CushingQoL score. Abbreviations: CSQoL, CushingQoL; MACS, mild autonomous cortisol secretion; MCS, mental component summary; PCS, physical component summary. Footnote: panels (A)–(D): 159 observations are available; panels (E) and (F): 154 observations are available.
Table 4.
Multivariable analysis of factors associated with the quality of life in patients with hypercortisolism.
| Variable | SF36 PCS | SF36 MCS | Standardized CushingQoL total score | Standardized CushingQoL psychosocial component | Standardized CushingQoL physical component |
|---|---|---|---|---|---|
| Estimate (P-value) | |||||
| Age (per year increase) | 0.204 (0.001) |
0.274 (<0.001) |
0.350 (<0.001) |
0.400 (<0.001) |
0.198 (0.114) |
| Sex (women) | −0.777 (0.704) |
−5.457 (0.020) |
−10.634 (0.002) |
−10.160 (0.006) |
−12.931 (0.002) |
| BMI (per 1 kg/m2 increase) | −0.402 (<0.001) |
−0.019 (0.872) |
−0.209 (0.225) |
−0.349 (0.061) |
0.264 (0.211) |
| Clinical severity score (per 1 point increase) | −0.776 (<0.001) |
−0.043 (0.813) |
−1.205 (<0.001) |
−1.000 (<0.001) |
−1.785 (<0.001) |
Abbreviations: BMI, body mass index; MCS, mental component summary; PCS, physical component summary; SF36, Short Form-36 questionnaire.
Discussion
In this study, we created clinical and biochemical scoring systems to characterize the severity of hypercortisolism in both patients with overt CS and those with MACS. We showed that patients with MACS and CS have similar impairment in muscle strength. While the physical components of quality of life measured through both CushingQoL and SF36 were lower in patients with CS vs MACS, fewer between-group differences were noted in the psychosocial component of CushingQoL and no difference in the mental component of SF36. Finally, we found that clinical severity score and not biochemical severity score was associated with proximal myopathy and quality-of-life measures.
We developed and applied a scoring system to assess clinical severity of hypercortisolism in patients with MACS and CS. Physical manifestations of CS present with a significant inter-individual variability with certain signs being rare but highly sensitive, such as wide purple striae, and other signs that could be present in patients without CS (truncal obesity, weight gain, facial rounding, and dorsocervical pad). The presence of certain comorbidities, such as hypertension, diabetes mellitus, osteoporosis, and obesity, is more prevalent in CS and MACS, but are present also in patients without hypercortisolism. As such, we hypothesized that creating a clinical scoring system that assesses both physical features and comorbidities in a standardized manner will be more sensitive than any one sign/combination of signs. We demonstrated that clinical severity score not only differentiates well between different subtypes of CS and MACS but is also associated with the quality-of-life measures and muscle strength.
We also developed a scoring system to assess the biochemical severity of hypercortisolism. This allowed us to classify patients who were tested with a variety of acceptable tests for hypercortisolism, as well as patients with MACS, who usually demonstrate normal 24-hour urinary free cortisol and late-night salivary cortisol measurements. As not all tests are positive even in overt CS, and there may be an intra-individual variability in test results, biochemical severity score may perform better in the association analyses than an individual test for hypercortisolism. Furthermore, as there is a difference in the individual susceptibility to hypercortisolism, we hypothesized that while there would be a correlation between the clinical and biochemical severity scores, clinical severity score would be more accurately associated with muscle strength and quality of life. In our study, we indeed were able to demonstrate the differences in the biochemical severity score of different subtypes of CS and MACS, and also showed a good correlation of clinical and biochemical severity scores. However, we found that, unlike the clinical severity score, the biochemical severity score was not associated with most quality-of-life outcomes and muscle strength.
We found that in patients with CS and MACS, sit-to-stand test was more abnormal than measurement of hand grip. This is likely due to predominant impact of hypercortisolism on proximal muscles, and as such more accurately assessed with the sit-to-stand test. We showed that the sit-to-stand test correlated with the clinical severity score, and both sit-to-stand test performance and hand grip strength were associated with the physical component of SF36. We also found that patients with MACS, despite the absence of overt features of CS, demonstrate similar impairment of muscle strength, potentially due to milder but longer unrecognized exposure to hypercortisolism. While there are several studies investigating muscle strength in overt CS,15,16,25,26 we found no studies evaluating muscle strength in patients with untreated MACS versus different CS subtypes.
Our study demonstrated that patients with hypercortisolism reported a substantially lower quality of life in all dimensions of SF36, when compared to a sex- and age-adjusted general population. These findings are in line with results from previous studies in other healthcare networks.9-14 In addition, we showed that patients with MACS had lower SF36 score in all domains of both physical and mental components when compared to the referent subjects. While on the CushingQoL, both the physical and psychosocial components were lower in CS as opposed to MACS, on SF36, only physical component was lower in patients with CS, while the mental component scores were similar. We further identified several factors, including younger age, female sex, higher BMI, and higher clinical severity, that independently correlated with one or more subcomponents of quality of life. Notably, physical components of quality of life were lower in patients with CS versus MACS, though muscle strength impairment was similar. This is possibly explained by a more gradual impairment in patients with MACS that allowed more time to adapt and compensate for the muscle strength loss.
Strengths of this study include consecutive prospective enrollment of patients, inclusion of patients with both overt CS and MACS, inclusion of age, sex, and BMI-matched referent subjects, and a large sample size, especially considering the rarity of CS. While the study did not dictate a particular hormonal workup, all assessments were performed by experienced endocrinologists with expertise in hypercortisolism. A standardized assessment that included both an interview and a focused physical exam allowed for careful assessment of physical features and metabolic abnormalities, as well as historical elements that were considered in the clinical severity score creation. Limitations include a potential selection bias and referral bias, especially for patients with MACS, as patients with CS are mostly assessed in the experienced tertiary centers. It is possible that patients may have more severe symptoms when compared to those in community settings and were more likely to receive subspecialized endocrine care. Therefore, the results of this study may not be applicable to populations outside referral centers, or outside the United States, or to non-White populations (as 92% of our study participants were White). Only hand grip analysis (and not sit-to-stand measurements) was available for referent subjects. Considering that all patients with MACS were diagnosed incidentally after serendipitous discovery with an adrenal mass, the duration of MACS was impossible to assess.
Conclusion
Patients with both mild and overt hypercortisolism experienced impaired muscle strength and reported substantially lower quality of life. Clinical severity score, and not the biochemical severity score, was associated with the quality of life and muscle strength impairment. Assessment of the clinical severity in patients with MACS may aid individualization of management.
Supplementary Material
Acknowledgments
The authors are grateful to the patients who volunteered to participate in this study and contribute to furthering understanding of endogenous hypercortisolism. We would also like to acknowledge the support from our colleagues in the Pituitary-Gonad-Adrenal Core Group at Mayo Clinic.
Contributor Information
Dingfeng Li, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN 55905, United States; Department of Endocrinology, Endocrinology and Metabolism Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, United States.
Catherine D Zhang, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN 55905, United States; Division of Endocrinology and Molecular Medicine, Medical College of Wisconsin, Milwaukee, WI, United States.
Jasmine Saini, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN 55905, United States.
Sumitabh Singh, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN 55905, United States; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USTW 75390, United States.
Rohit Nathani, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN 55905, United States; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USTW 75390, United States.
Karthik Thangamuthu, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN 55905, United States.
Malavika Suresh, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN 55905, United States; Department of Internal Medicine, Medstar Health, Baltimore, MD, medstar: 21230, United States.
Elizabeth J Atkinson, Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, United States.
Sara J Achenbach, Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, United States.
Jamie Van Gompel, Department of Neurosurgery, Mayo Clinic, Rochester, MN 55905, United States.
William F Young, Jr, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN 55905, United States.
Irina Bancos, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN 55905, United States.
Supplementary material
Supplementary material is available at European Journal of Endocrinology online.
Funding
This research was partially supported by the philanthropic gift from Lili and Keith Olin supporting patients with Cushing syndrome and by the grant from Recordati in support of investigator-initiated project on glucocorticoid withdrawal syndrome. I.B. was also partially supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) USA under awards K23DK121888 and R03DK132121. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Conflicts of interest: D.L. is currently an employee of BridgeBio, which is unrelated to the submitted work. I.B. reports advisory board participation/consulting (fees to institution) with HRA Pharma, Corcept, Recordati, Sparrow Pharmaceutics, Neurocrine, Spruce, and Diurnal outside the submitted work, and data monitoring and safety board participation for Adrenas. Coauthors (I.B.) are on the editorial board of EJE. They were not involved in the review or editorial process for this paper, on which they are listed as authors. The remainder of the authors have nothing to disclose.
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