INTRODUCTION

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Cushing's syndrome leads to muscle weakness, particularly of the proximal limb muscles. However, the effect of long-term elevation of endogenous steroids on the respiratory muscles in Cushing's syndrome has not been assessed.

High dose exogenous corticosteroids have been found to cause respiratory muscle weakness in both animals (1) and humans (2). However, studies of corticosteroid therapy are often complicated by the effect of the original disease process on respiratory muscle and lung function.

Corticosteroids particularly affect muscles that are inactive, proximal and contain a predominance of type 11b (fast) fibers (3). Although Type 11b fibers are relatively sparse in the diaphragm (6) some animal studies, using high prednisolone dosages, have shown a loss of diaphragm mass (1), whereas lower doses did not have this effect (7, 8).

In patients, short-term high dose prednisolone therapy (60 mg/d for 8 wk) reduced maximal inspiratory pressure (MIP) and muscle endurance (9). Severe respiratory muscle weakness has been reported in three patients who had received 80, 60, and 32 mg of prednisolone during an exacerbation of asthma or COPD (10). Long-term administration of prednisolone (mean, 10 yr) at a lower dose (13 mg/d) had no effect (11), although 4 mg/d of prednisolone in patients with COPD taken over a period of 6 mo was enough to reduce both MIP and maximal expiratory pressure (MEP) (2). Fluorinated steroids may have a greater effect on muscle strength (12).

The effects of corticosteroids on muscle appear related to dose, type of steroid, duration of exposure, and muscle fiber type. The impact on the respiratory muscles of prolonged exposure to elevated levels of endogenous steroids in spontaneous Cushing's syndrome was therefore hard to predict. We aimed to establish whether respiratory muscle weakness was a feature of Cushing's syndrome.

	METHODS

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Ten consecutive patients referred to a tertiary endocrine center with clinical and biochemical features consistent with Cushing's syndrome were recruited into the study. All demonstrated a serum cortisol above 50 nmol/L despite the administration of 0.5 mg dexamethasone every 6 h for 48 h. Nine patients had pituitary ACTH-dependent disease and one had ectopic ACTH from a bronchial carcinoid tumor. All gave informed consent, and the study was approved by the local ethics committees. Measurements were made before the start of medical or surgical treatment and repeated in four patients 12 mo after the completion of treatment. On each occasion these measurements were repeated until consistency was obtained. To maintain patient cooperation it was not possible to repeat sustained measurements as many times as short sharp dynamic maneuvers.

Measurements

Respiratory muscle strength. Respiratory muscle strength was assessed using maximal static mouth pressures and pressures generated during maximal sniffs. MIP and MEP maintained for at least 1 s were measured during maximal voluntary efforts at residual volume (RV) and TLC, respectively (13). A noseclip and flanged mouthpiece were used. The best of five reproducible efforts was chosen (2). Maximal sniff esophageal (max sniff Pes) and transdiaphragmatic (max sniff Pdi) pressures (14) were measured via a pair of 110-cm balloon catheters passed pernasally with 2% lignocaine anaesthetic gel and positioned in the esophagus and stomach (15, 16). The best of 20 reproducible sniffs was recorded. The esophageal pressure trace was compared with the baseline resting level to confirm that sniffs were performed from the same baseline Pes on each occasion. Pressures were measured in cm H₂O by Validyne MP45 differential transducers (Validyne Corporation, Northridge, CA) and recorded using LabView 2.2 software (National Instruments, Austin, TX).

Pulmonary function testing. FEV₁ and FVC were measured using a heated pneumotachograph with integrated flow signal for volume (Jaeger UK Ltd, Market Harboro, UK). The results were expressed as a percentage of predicted values (17).

Quadriceps strength. Quadriceps strength was measured using a purpose-built chair with the back rest positioned to allow for the different femur lengths of the patients while providing adequate support for the patient's back (18, 19).

Patients sat with their knees flexed to 90 degrees and their ankles hooked through an indistensible strap attached to a strain gauge. They were asked to forcefully extend their leg at the knee against this resistance using maximum effort. The force exerted was measured, and the process was repeated until three consistent results were obtained. The best results for each leg were recorded.

	RESULTS

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The characteristics of the 10 patients are shown in Table 1 and those of the four patients who were retested are shown in Table 2. None of the patients was hypercapnic. All patients had a proximal myopathy on clinical examination. Quadriceps strength was reduced in all patients, with a mean value of 49% of predicted (Table 3) (18).

MIPs (mean, 92 cm H₂O; 105% of predicted) and MEPs (mean, 134 cm H₂O; 78% of predicted) in nine patients were less than one standard deviation below the normal mean (13). The patients produced maximal sniff Pdis within two standard deviations of the normal mean, with a mean sniff Pdi of 107 cm H₂O (78% of predicted) (Table 1). One male patient (Table 3) (Patient 8) had a maximal sniff Pdi of 92 cm H₂O (62% of predicted and below two standard deviations from the normal mean) (14). Mean sniff Pes for the group of 10 patients was 92 cm H₂O (92% of predicted). The lower limit of normal for sniff Pdi (defined as 2 SD below the normal mean) is 100 cm H₂O for men and 71 cm H₂O for women, and for sniff Pes it is 54 cm H₂O for men and 49 cm H₂O for women (14).

Circulating androgen levels were not elevated in any of the patients.

Repeat Muscle Tests after Surgery

Respiratory muscle tests were repeated in four patients 12 mo after surgery (Table 2). Cortisol levels had returned to normal. The quadriceps muscles had increased in strength in all subjects (mean increase, 27%), although they had not returned to predicted normal levels. Maximal expiratory mouth pressures improved slightly, whereas MIPs fell. One patient (Patient 1) who had the largest improvement in quadriceps strength also demonstrated an increase in MIPs, MEPs, and max sniff Pdi. Overall respiratory muscle strength showed less change than quadriceps strength.

	DISCUSSION

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We found no evidence of clinically significant respiratory muscle weakness in our patients. Inspiratory and expiratory muscle strength was within the normal range during volitional testing in nine of 10 subjects.

Patient 8 showed the lowest respiratory muscle strength and the most severe quadriceps weakness. Although his mean cortisol levels were fourth highest, he demonstrated the second highest body mass index (BMI) of 33. The one other patient with a comparable BMI of 35 also demonstrated severe proximal myopathy affecting the quadriceps, although of lesser duration. Patient 8 may therefore have had severe disease for 3 yr. Some patients find maximal volitional maneuvers difficult, especially when they are unwell. Therefore, we recorded several measures of respiratory muscle strength, including max sniff Pes, which proved to be normal, indicating that his inspiratory muscle strength was also normal. The relatively lower sniff Pdi in the face of a normal sniff Pes is sometimes observed in normal subjects and patients, probably because of their sniffing technique.

The duration of symptoms in the 10 patients with Cushing's syndrome was on average between 2 and 3 yr, so they had been exposed to elevated levels of circulating corticosteroids for prolonged periods. The mean daily circulating cortisol value was approximately 2.2-fold greater than normal. Such cortisol levels are approximately equivalent to a dose of prednisolone of 17 mg/d.

There was no systematic improvement in inspiratory muscle strength among the small number of patients in whom measurements were repeated, although Patient 1, who showed the greatest improvement in quadriceps strength (63%), also showed some improvement in MIP, MEP, and max sniffs. Overall the pretreatment measurements were normal; however, we cannot exclude the possibility that the patients could have been slightly stronger before they became ill. The expiratory muscles, which do not normally contract during tidal breathing, were capable of producing normal MEPs, but did show a small improvement (mean increase, 9%) in the four patients who were retested. Quadriceps strength was reduced in all patients and indeed showed a mean improvement of 27% in the four patients who were retested.

Overall therefore, Cushing's syndrome had a greater effect on quadriceps strength than on respiratory muscle strength. The reasons for this are not clear. It may be that repeated contraction of the inspiratory muscles on a continuous basis is protective (7). However, the differences between the abdominal muscles and the quadriceps are far less clear and so do not fit this explanation well. Differences in muscle fiber type or blood supply may influence the impact of corticosteroids. It may be that endogenous steroids have less effect on respiratory muscle strength than therapeutic corticosteroids (12).

In summary, these 10 patients with Cushing's syndrome and marked quadriceps weakness had inspiratory muscle strength within or at the lower end of the normal range. Expiratory muscle strength was also normal, although a small increase was seen on retesting after therapy.

We conclude that substantial reductions in respiratory muscle contractility are not a usual feature of severe Cushing's syndrome even when associated with proximal limb myopathy.