Hyperthyroidism is associated with a general muscle weakness, which is part of the initial clinical manifestation of about 80% of patients(10). In addition, this skeletal muscle dysfunction can be severe in patients newly diagnosed with Graves' disease, compromising the patient's capability to perform simple daily activities such as self-care tasks (10). While skeletal myopathy decreases the quality of life for these patients, medical treatment has significantly improved muscle performance and increased strength up to 40% when patients were tested in the euthyroid state. (1).
Several studies have demonstrated lower glycogen content(1), decreased activity of oxidative enzymes(5,8), changes in fiber-type composition(7,15), and a more pronounced phosphocreatine depletion and pH fall in skeletal muscles during dynamic contractions(4) in both human and experimental animals with hyperthyroidism. These structural and biochemical changes suggest that alterations in the intrinsic contractile properties of muscle can explain at least partially the clinically relevant weakness and impaired exercise tolerance in patients with Graves' disease.
Another important component of the hyperthyroid myopathy is muscle atrophy, which seems to affect more proximal than distal muscle groups(10). Muscle atrophy is a contributing factor for the decrease in absolute muscle strength. Although decreased muscle mass during thyrotoxicosis and the recovery of muscle mass after medical treatment is a well-known clinical feature of hyperthyroidism(1,8-10), a systematic assessment of the longitudinal changes in body composition of this group of patients is currently unavailable. This information would be useful not only to better understand the effects of thyroid dysfunction on the distribution of adipose tissue and lean body mass but also to determine whether the changes in skeletal muscle performance that occur along the course of the disease and treatment result from modifications in intrinsic muscle function independent of muscle mass changes.
The purpose of this study was to assess body composition and skeletal muscle function of patients with hyperthyroidism before and after pharmacological treatment to determine the contribution of changes in skeletal muscle mass toward the modifications in muscle function.
Patients. Data were collected from seven women and two men (mean± SE age 39 ± 4 yr) referred to the Endocrinology Out-Patient Clinic at the University Hospital. All patients presented with clinical diagnosis and laboratory confirmation (Table 1) of Graves' disease, including diffuse goiter, but none had severe infiltrative ophthalmopathy. No other concurrent diseases were present. The patients were informed about the procedures and risks of the experiments and provided signed informed consent before entering the study. The appropriate size of the sample was determined by calculations using the results of preliminary experiments and setting the power of the statistical tests to 0.8 and the alpha error to 0.05. An age and gender-matched control group (N = 9; age 37 ± 4 yr) was also submitted to skeletal function tests and anthopometric measurements.
Protocol. After the diagnosis was established, the patients were submitted to anthropometric measurements and skeletal muscle performance tests(see below). These tests occurred on the same day. Following this initial evaluation, patients underwent monotherapy with oral propranolol (initial dose 80-240 mg·d-1) for an average period of 1 wk (8 ± 0.3 d) before a second evaluation was performed. After the second evaluation, antithyroid therapy was initiated (propylthiouracil 400-1000 mg·d-1 oral or methimazole 40-48 mg·d-1 oral). Patients were submitted to periodical clinical and laboratory evaluations until the euthyroid state was achieved (Table 1). At this point (182 ± 31 d), a third assessment of body composition and muscle function was conducted. Patients did not change the level of daily physical activity and no other disease was detected during the entire period of the study.
Skeletal muscle function. Maximal static strength and endurance for hip flexion, ankle dorsiflexion, and handgrip of the right side were determined using dynamometers for handgrip (Therapeutic Instruments, Clifton, NJ) and for hip and ankle movements (Takei Kiki Kogyo, Tokyo, Japan). Maximal static strength was defined as the highest peak force generated by the muscle group during three separate trials each lasting 2-5 s with the patients in a sitting position with the joint positioned at a 90° angle (hip and ankle flexion). For handgrip, the patients were seated with the arm stretched along the trunk. To calculate muscle endurance the patients were asked to sustain a load equivalent to 30% of the maximal force for as long as they could without changing the joint angle.
Body composition. Anthopometric measurements included stature, body weight, skinfold thicknesses using a Harpenden caliper (triceps, subscapular, biceps, iliac crest, supraspinal, abdominal, front thigh, and medial calf), circumferences using a nonelastic tape (arm relaxed, arm flexed and tensed, forearm, wrist, chest, waist, gluteal, thigh, calf, and ankle), and bone widths measured with a modified Mitutoyo caliper (distal humerus and femur). The measurement protocol was guided by standard anatomical landmarks and conventions (11). Triplicate measurements were obtained at each skinfold or circumference site and the median values were taken for analysis.
Different procedures were applied to the original data to assess physique status and provide indexes of body composition and fat distribution. The sum of skinfold thicknesses was used to estimate subcutaneous fat mass; limb circumferences (arm, thigh, and calf) were skinfold-corrected to yield muscle circumferences, which were added together to provide an index of limb muscle mass. A linear geometric model (3) was used to obtain muscle circumferences by applying the formula: muscle circumference = limb circumferences - (π · limb skinfold).
Statistical analysis. Univariate tests were initially applied to verify whether the data were normally distributed and hence to determine the adequacy for using parametric procedures. In the case of normal distributions, one-way repeated measures analysis of variance (ANOVA) followed by the Student-Newman-Keuls' tests where appropriate were applied to compare the results obtained before treatment, at the end of propranolol monotherapy, and in the euthyroid state. The Friedman repeated measures ANOVA on ranks was used for the comparisons as the nonparametric equivalent test when needed. Comparisons between the results from the patients and the control group were performed by the Student t-test followed by Bonferroni correction. Pearson product-moment correlation coefficients were calculated to determine the association between variables, and the equation describing their relationship were yielded by linear regression analysis. Data are presented as mean ± SE; P < 0.05 was considered to be statistically significant.
Body weight was 53.4 ± 3.2 kg before treatment and changed to 54.3± 2.8 kg after 1 wk of oral propranolol administration and to 58.2± 2.9 kg after antithyroid treatment (F = 7.8; P = 0.004;Fig. 1). There was a trend for the sum of skinfold thickness to increase (from 13.0 ± 2.1, to 13.4 ± 2.1 after propranolol and to 15.0 ± 2.8 cm at the end of the study F = 3.7;P = 0.052; Fig. 1). In addition, the sum of skinfold-corrected limb circumferences, used as an index of limb muscle mass, changed from 90.7 ± 3.1 to 90.9 ± 3.6 to 94.4 ± 3.1 cm after correction of the hyperthyroidism (F = 8.2; P = 0.017;Fig. 1).
Both muscle strength and endurance of the three muscle groups increased significantly when the patients were evaluated in the euthyroid state. The results of the muscle function tests were corrected with the sum of skinfold-corrected limb circumferences used as an index of muscle mass. The linear correlations between skinfold-corrected limb girths and handgrip strength and endurance are depicted in Figure 2. Significant correlations were also observed for hip flexion (strength: r = 0.50, P = 0.008; endurance: r = 0.56, P = 0.003) and for ankle dorsiflexion (strength: r = 0.50, P = 0.007; endurance: r = 0.51; P < 0.006).
The results of the muscle function tests were adjusted for the changes in muscular girths and the beneficial effect of treatment was still evident(Figs. 3 and 4). Figure 3 shows the effect of medical treatment on maximal static strength of three movements in the nine patients with hyperthryoidism. Maximal strength of ankle dorsiflexion (panel A) was lower than for controls at the first evaluation (t= 2.9; Pc = 0.033) and increased significantly after treatment (F = 13.6; P = 0.001). For hip flexion (panel B) although the results from the patients at all evaluations were similar to controls(P > 0.05), maximal strength increased after treatment (F = 4.3;P = 0.033). The same trend was observed for handgrip (panel C).
Muscle endurance for the three movements were lower in the patients than in controls at all three evaluations (P < 0.05;Fig. 4). However, there was a significant increase in muscle endurance for the three movements studied after correction of the hyperthroidism.
The results of this study demonstrated that the increased body weight after medical treatment of patients with hyperthyroidism is associated with an increased sum of skinfold-corrected limb circumferences, an index of muscle mass. In addition, static strength and endurance of three different muscle groups improved after treatment, and this improvement persisted after strength and endurance were adjusted for the increase in the sum of skinfold-corrected limb circumferences.
Decreased body weight is a typical finding in patients newly diagnosed with hyperthyroidism (10). Although the reduced body weight is believed to result from a reduction in skeletal muscle mass(1), as far as we know the present study is the first to use objective measurements to describe the relative changes in muscle and adipose tissue mass after treatment with antithyroid drugs. The results showed that although subcutaneous adipose tissue mass may contribute to the recovery of body weight after treatment, the greater muscle mass, as indicated by the significant larger sum of skinfold-corrected limb circumferences, accounted for the increase in body weight.
Previous studies have shown impairment of skeletal muscle function in patients with hyperthyroidism, which tends to resolve after medical treatment(1,8,9,14). However, these studies raised the question of whether the recovery in muscle function resulted from amelioration of intrinsic contactile properties of skeletal muscle or whether it was a simple consequence of the increased muscle mass. The present findings show that both greater muscle mass and improved muscle function contribute to the recovery of muscle performance. However, the mechanisms through which correction of hyperthyroidism improves muscle performance remains to be determined. Although it was not the purpose of this study, it could be speculated that the impaired intrinsic muscle function and its recovery after treatment resulted from changes in the metabolic profile of skeletal muscle(4,5,7,15), alteration of the nervous control of skeletal muscle (6), and promotion or inhibition of the expression of various genes coding for contractile proteins(2,12).
In general, the patients in this study improved muscle function. Maximal static strength was comparable between the control group and the patients at the end of the study, i.e., in the euthyroid state. On the other hand, muscle endurance did not reach the control values. Actually, the impairment in muscle endurance was clearly more profound than in maximal static strength. This finding may have practical clinical implications as muscle endurance was defined as the maximal time a given load can be sustained and therefore is believed to be closely related to the capability to perform daily life activities. From these results, it can be suggested that achieving the euthyroid state should not be considered a landmark for assuming that all aspects of muscle function - strength and endurance - have normalized.
Monotherapy with propranolol during 1 wk produced a significant improvement for handgrip performance only. However, a trend for a higher maximal static strength of hip flexion and muscle endurance of handgrip and hip flexion was observed. These results suggest that the hyper-catecholaminergic state presented in patients with Graves' disease plays a role in producing the impairment in skeletal muscle function. This improvement in muscle strength produced by β-adrenergic blockade has been shown in humans by Olson et al. (9) although Zaiton et al. (16) failed to demonstrate this effect in experimental hyperthyroidism induced in rats. The reports by Seger et al. (13) and Olson et al.(9) have shown that the positive effect of propranolol on muscle function does not result from a training effect. In these studies, a group of healthy subjects showed no increases in the muscle testing results over three repeated test sessions (13) or after 1 wk of propranolol administration (9). Similarly, it is unlikely that in the present study the increased muscle strength and endurance after the pharmacological treatment represented a training effect since the patients were retested only 6 months later. In our group of patients, the improvement in muscle function was detected after only 1 wk of propranolol monotherapy, whereas the influence of antithyroid was tested after 6 months of treatment. Therefore, the relatively smaller effect of propranolol than of antithyroid drugs may not represent the true relative impact of each drug on muscle performance in hyperthyroid patients.
Although the subjects in the control group were gender and age matched with the patients, the results from their muscle function evaluation may not represent normal values for the population. However, the comparison between patients and controls showed that muscle endurance was more affected than maximal static strength. This conclusion is supported by the longitudinal evaluation in which each patient served as his/her own control.
In conclusion, the results of the present study demonstrated that the increased body weight after medical treatment of patients with hyperthyroidism is mainly a result of a greater muscle mass. This increase in skeletal muscle mass contributed to the improved muscle static strength and endurance. However, an improvement of intrinsic contractile function also occurred over the period of treatment and seems to be the main factor in producing a better muscle performance.
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