Effects of Physical Activity on Body Composition and Fatigue Perception in Patients on Thyrotropin-Suppressive Therapy for Differentiated Thyroid Carcinoma

Abstract

Background:

Subclinical thyrotoxicosis (scTox) may be associated with alterations in body composition and fatigue that can be possibly reversed with physical activity. The aim of the present study was to evaluate whether the systematic practice of physical activity improves lower extremity muscle mass and fatigue perception in patients with scTox.

Materials and Methods:

We studied 36 patients (2 men) with median age of 48.0 (43.0–51.0) years, body mass index of 27.4 (22.1–30.2) kg/m², thyrotropin <0.4 mU/L, and free thyroxine between 0.8 and 1.9 ng/dL and 48 control subjects (C group; 7 men). Patients were randomly divided in two groups according to the adherence to the exercise training: scTox-Tr (n = 19)—patients who adhered to the exercise intervention and scTox-Sed (n = 17)—patients who did not adhere to it. The C group did not participate in the randomization. The exercise training was supervised by a physical education instructor, and it was composed of 60 minutes of aerobic activity and stretching exercises, twice a week, during 12 weeks. In both groups, body composition was assessed (anthropometric method), and the Chalder Fatigue Scale was determined at baseline and after 3 months of intervention (scTox-Tr group) or observation (scTox-Sed group).

Results:

At baseline, patients with scTox had lower muscle mass and mid-thigh girth and more fatigue on the Chalder Fatigue Scale than euthyroid control subjects. The scTox-Tr group had an increase in muscle mass, reduction in the variables reflecting whole body fat, and lesser perception of fatigue during the exercise training period (p ≤ 0.05 for these parameters at the start and end of the exercise training period).

Conclusions:

scTox is associated with lower muscle mass and mid-thigh girth and more fatigue. Physical activity training can partially ameliorate these characteristics. More studies are needed to determine what training program would be optimum, both in terms of beneficial effects and for avoiding potential adverse responses.

Introduction

D ifferentiated thyroid carcinoma (DTC) accounts for 90% of all thyroid malignancies (1). In the last decades, there has been an increase in the incidence of DTC, possibly as a result of improved diagnostic methods and their more widespread use. Thyroid nodules are very common, though only about 5%–10% of them are malignant. The conventional treatment for DTC consists of total or partial thyroidectomy, often followed by ablation of the thyroid remnants with 131-I. Following these procedures, patients require levothyroxine (LT₄) treatment (2), and currently most are given doses that suppress serum thyrotropin (TSH). Therefore, LT₄ treatment in patients with a history of DTC is a common cause of so-called subclinical hyperthyroidism (subclinical thyrotoxicosis [scTox]), which is characterized by serum TSH concentrations that are low with normal serum free T4 (FT₄) and free triiodothyronine concentrations (3). Epidemiological data indicate a wide variation in the prevalence of scTox, from less than 1% to about 16%. Among other things, it is influenced by gender, the underlying disease, age, the assignment for what the lower limit of the normal range for TSH is, and the methods used to measure serum TSH concentrations (4 –6). Cardiovascular, neuromuscular, and psychological alterations have been described in scTox, and many clinical parameters have been evaluated (7).

Patients with overt thyrotoxicosis have changes in lean and fat body mass and bone mineral density. After restoration of the euthyroid state with treatment, these changes are reversible (8 –10). Fatigue, weakness, and tiredness occur in overt thyrotoxicosis and are due, at least in part, to distal muscle dysfunction. They are present in ∼80% of patients (9) and impair daily work and other activities, contributing to a decrease in quality of life.

There is little information regarding body composition or fatigue in patients with scTox, particularly in those in whom it is due to administration of supra-physiological amounts of thyroid hormone. The aim of the present study was to determine parameters of body composition and the degree of fatigue in patients with scTox due to thyroid hormone administration and to evaluate the effect of increasing physical activity on this.

Materials and Methods

Study and sample

Two studies were performed. The first was a cross-sectional study of the body composition and the fatigue perception of patients with scTox in comparison to control subjects (C). The second was a prospective study of physical activity intervention in the patients with scTox.

A total of 34 women and 2 men who were followed at our Endocrine Clinic for DTC were included in the study. All patients with scTox were on TSH-suppressive therapy with LT₄ and had scTox for at least 6 months before the study. The other inclusion criteria for the scTox group were that the age of the patients should be 18 or more, the serum TSH should be less than 0.4 mU/L, the FT₄ should be between 0.8 and 1.9 ng/dL, and the patients should be following a sedentary lifestyle for at least 6 months. Serum TSH and FT₄ were determined by commercial methods (Immulite; Diagnostic Products).

The C group for the study was composed of 7 men and 41 women with normal TSH and FT₄ levels and no history of thyroid disease. They also had sedentary lifestyle in the 6 months before inclusion in the study.

Patients or controls with any chronic and/or cardiovascular disease (even if treated), those who were taking drugs that could interfere with thyroid status, and those with muscle and joint alterations that could limit physical activity, as prescribed in this study, were excluded. Patients with scTox with positive total body radioiodine scan or detectable serum thyroglobulin were also excluded. The protocol was approved by the local ethics committee, and both groups gave their written consent before study entry.

Study protocol

An initial cross-sectional study of both patient and C subjects was performed to provide information about illness history, menopause and health-related habits, and a history of fatigue perception. A cardiopulmonary symptom-limiting exercise test (treadmill; Modified Balke protocol) (11) was also performed. Patients and C subjects were not included in the study if a severe alteration was present in blood pressure, heart rate, or electrocardiogram. Data from the previous 6 months regarding thyroid function tests of patients with scTox were obtained from the medical record. Further, a new assessment of serum hormonal levels (serum TSH and FT₄) was obtained from all participants at the time of inclusion.

After these procedures, the study subjects had determination of their body composition at the Exercise Physiology Laboratory of the Physical Education and Sports School, of the Federal University of Rio de Janeiro, Brazil.

In the prospective phase of the study, the patients with scTox were randomized in a non-blinded fashion to either participate or not participate in a physical activity program. The groups and subgroups were defined as follows. Patients with scTox who participated in the program were designated scTox-Tr. Patients with scTox who did not participate in the program were designated scTox-Sed. The physical activity program consisted of aerobic and stretching activities twice a week for 12 weeks. This was supervised by the authors. The patients with scTox-Sed were advised to keep themselves physically inactive during this period.

After a period of 3 months of training or observation, the studies of body composition, fatigue perception, and cardiopulmonary function that were done at baseline were repeated.

Body composition

Body composition was assessed by the anthropometric method, according to the procedures proposed by the International Society for Advancement in Kinanthropometry (ISAK) (12). The following measures were taken: (i) breadths: biepicondylar humerus, biepicondylar femur, and bistyloid (0.1 mm; small sliding caliper; Cescorf); (ii) skinfolds thickness: triceps, biceps, subscapular, iliac crest, media axillary, abdominal, front thigh, medial calf, and chest (0.1 mm; skinfold caliper; Cescorf); (iii) girths: waist, hip, abdominal, mid thigh, and calf (1 mm; flexible steel tape; Sanny); (iv) weight (0.1 kg; scale; Filizola); and (v) height (1 cm; stadiometer; Filizola).

The following parameters were calculated: body mass index (BMI; kg/m²), the sum of nine skinfolds thickness (Σ9_SK; mm), waist–hip ratio (WHR), body fat percentage (%BF) (13 –15), lean mass (obtained from the total weight and the fat mass; kg), bone mass (kg) (16), residual mass (kg) (17), and muscle mass (obtained from the total weight and bone, residual and fat mass; kg). Patients and C subjects were classified regarding BMI, WHR, and %BF according to standard patterns (13,14,18,19).

Subjects wore minimal clothing (one piece for men and two pieces for women), without shoes or stockings, when anthropometric measurements were taken. All measurements were made by the same skilled anthropometrist. The intraclass correlation coefficients of the anthropometric variables measured varied from 0.8 to 1.0.

Fatigue perception

The translated and validated Chalder Fatigue Scale (20) was used to evaluate fatigue perception. This is a self-administrated instrument that comprises 16 questions that measure three aspects of fatigue. These are the presence of mental and physical fatigue, tiredness, weakness in the past 4 weeks (11 questions), muscle pain (2 questions), and fatigue qualification (3 questions). Answers are presented on a Likert scale, varying between 1 and 4 points. Higher scores are associated with higher impairment. The internal consistency of the 11 questions of the scale, as well as muscle pain and fatigue qualification, were assessed with the Cronbach Alpha Coefficient (21).

Physical activity program

The physical activity program was aerobic activity performed on a treadmill under the supervision of a physical education instructor. The frequency of training was twice a week, for 12 weeks. Each session of aerobic activity lasted 60 minutes, divided in three phases: warm up (5 minutes), main part (50 minutes), and cool down (5 minutes).

Training was prescribed individually, based on the patient's performance in the cardiopulmonary test, the predicted maximum heart rate (HR_max = 220−age), and the patient's initial physical condition. Intensity was monitored by HR, and it was modified according to the performance of each patient, keeping the HR between 65% and 75% of HR_max, but under the anerobic threshold HR (obtained in the cardiopulmonary test). Training could be continuous (walking, walking with inclination, or running) or intermittent (walking/running or walking/walking with inclination).

The HR was monitored throughout training with a HR monitor (Polar), the blood pressure was measured every 10 minutes, and the subjective perception of effort (Borg Scale) was provided by the participant. At the end of the aerobic exercise, patients underwent a cool down period comprised of stretching exercises for the principal muscle groups involved in the activity. Patients were advised to drink adequate fluids during training.

Statistical analysis

Descriptive analyzes are shown as median and 25^th and 75^th percentiles (interquartile range) for continuous variables and as relative frequency for categorical variables. At baseline, comparisons between patients and controls were made using the Mann–Whitney U-test. Fisher's exact test was used to compare prevalence relating to menopause and gender status. To analyze the impact of the exercise training or observation, the Wilcoxon Test was used to compare scTox-Tr_baseline versus scTox-Tr_3months and scTox-Sed_baseline versus scTox-Sed_3months. The use of nonparametric statistical tests was based on the sample size of each group. All analyses were performed using the software SPSS 13.0 for Windows (SPSS, Inc.), and statistical significance was assigned whenever the p-value was equal or less than 0.05.

Results

Sectional study

The baseline general characteristics, body composition variables, and Chalder Fatigue Scale scores of the patients with scTox and the C subjects are shown in Table 1. There were no differences between these two groups with regard to age, menopause status, or gender. Patients with scTox and C subjects differed in terms of muscle mass, this being greater in C subjects than in patients with scTox (p ≤ 0.05). C subjects also had greater mid-thigh girth than did patients with scTox (p ≤ 0.05). The median Σ9_SK and %BF were not different between the patients with scTox and the C subjects. About 54.1% of the C subjects and 61.2% of the patients with scTox had a %BF over the predicted values according to age and gender (p = 0.66) (13,14).

Table 1.

Baseline General Characteristics, Body Composition Variables, and Chalder Fatigue Scale Scores of Patients with Subclinical Thyrotoxicosis and Control Subjects

	Patients with scTox (n = 36)	Control subjects (n = 48)
Age (years)	48.00 (43.00–51.00)	50.50 (40.25–56.00)
Male (n; %)	2 (5.6)	7 (14.6)
Menopause (n; %)	15 (41.7)	22 (45.8)
TSH (mU/L)	0.02 (0.01–0.06)	1.56 (1.09–2.39)^a
FT₄ (ng/dL)	1.76 (1.43–1.88)	1.19 (1.03–1.32)^a
Disease's duration (years)	6.00 (4.00–9.75)	—
Weight (kg)	69.10 (57.20–76.23)	69.00 (61.53–73.98)
BMI (kg/m²)	27.39 (22.12–30.18)	27.09 (23.48–30.31)
Σ9_SK (mm)	234.20 (150.50–267.78)	201.7 (151.4–224.50)
%BF (%)	35.64 (25.90–39.16)	32.30 (26.07–34.61)
WHR	0.813 (0.762–0.862)	0.825 (0.733–0.870)
Lean mass (kg)	44.08 (41.35–49.63)	46.65 (43.51–51.18)
Bone mass (kg)	9.01 (8.47–9.94)	9.57 (8.42–10.45)
Muscle mass (kg)	21.19 (18.88–24.43)	23.23 (20.30–24.80)^a
Residual mass (kg)	14.44 (11.95–15.93)	14.44 (12.79–15.49)
Abdominal girth (cm)	93.95 (82.95–102.63)	92.05 (84.73–103.18)
Mild-thigh girth (cm)	51.70 (47.33–55.90)	53.53 (50.63–56.88)^a
Calf girth (cm)	35.45 (33.73–39.35)	36.45 (34.55–39.38)
Chalder Fatigue Scale	28.50 (24.00–35.00)	21.00 (19.00–25.00)^a
Muscular pain	5.00 (4.00–6.00)	4.00 (3.00–5.75)^a
Qualification of fatigue	5.00 (4.00–6.00)	3.00 (2.00–3.00)^a

Mann–Whitney U-test; patients with scTox versus control subjects; statistical significance: p ≤ 0.05

BMI, body mass index; FT₄, free thyroxine; Σ9_SK, sum of nine skinfolds thickness; %BF, body fat percentage; WHR, waist–hip ratio; scTox, subclinical thyrotoxicosis; TSH, thyrotropin.

The difference in the median values for BMI, WHR, and abdominal girth between the patients with scTox and the C subjects was not significant. The median BMI of both groups was “overweight” (pre-obese), according to the World Health Organization definition (18), and the median value of WHR and abdominal girth indicated central obesity (19).

In C subjects, there was a trend toward a greater lean mass (p = 0.07) in comparison to patients with scTox. The muscle mass of the patients with scTox was lower than that of the C subjects (p = 0.05); the bone mass of the patients with scTox was not different (p = 0.30) than that of the C subjects.

Patients with scTox and C subjects took the Chalder Fatigue Scale evaluation. The internal consistency of the responses to the 11 questions of the questionnaire was considered satisfactory (α = 0.9) (21). An adequate internal consistency was also present in the responses to the two questions concerning muscular pain (α = 0.7) and in the responses to the three questions concerning fatigue qualification (α = 0.7). This result means that the sample reported high level of consistency between the responses to the questions of the questionnaire.

Patients with scTox and C subjects were different with regard to fatigue perception, assessed by the Chalder Fatigue Scale, with worse results for patients with scTox (p < 0.01). The two groups also differed in the aspects of muscular pain (p < 0.01) and fatigue qualification (p < 0.01), with higher median values in patients with scTox than in C subjects (Table 1).

Not-blinded randomized controlled trial

Comparability between the two prospective groups

At baseline, there were no differences between patients with scTox-Tr and those with scTox-Sed regarding age (p = 0.28), menopause status (p = 0.16), gender (p = 0.93), TSH (p = 0.78), and FT₄ (p = 0.82) serum levels, and all variables related to body composition. Patients with scTox-Tr and scTox-Sed also had the same scores in Chalder Fatigue Scale (p = 0.41), muscular pain (p = 0.34), and qualification of fatigue (p = 0.98) (Table 2).

Table 2.

Body Composition Variables and Chalder Fatigue Scale Scores of Patients with scTox-Tr and scTox-Sed at Baseline and After 3 Months of Exercise Training or Observation

	scTox-Tr (n = 19)		scTox-Sed (n = 17)
	Baseline	3 months	Baseline	3 months
Weight (kg)	66.40 (54.30–75.40)	66.10 (54.00–73.50)^a	71.60 (60.35–77.25)	71.80 (61.25–78.35)
BMI (kg/m²)	26.37 (21.80–29.64)	26.58 (21.83–29.19)^a	28.05 (22.33–31.48)	28.38 (22.50–31.48)
Σ9_SK (mm)	237.20 (146.80–263.70)	216.30 (135.90–250.60)^a	231.20 (166.20–310.80)	235.00 (172.30–313.80)^b
%BF (%)	35.88 (25.33–38.66)	34.51 (23.84–37.36)^a	35.40 (28.52–42.13)	36.16 (28.45–42.57)^b
WHR	0.789 (0.738–0.856)	0.799 (0.721–0.841)	0.833 (0.772–0.891)	0.843 (0.764–0.899)
Lean mass (kg)	43.03 (37.21–48.23)	43.49 (38.31–49.31)^a	44.83 (42.14–50.31)	44.47 (41.87–48.92)
Bone mass (kg)	8.87 (8.29–9.99)	8.89 (8.37–10.32)	9.46 (8.76–9.99)	9.45 (8.87–9.77)
Muscle mass (kg)	19.75 (18.83–24.58)	21.90 (19.85–24.43)^a	21.62 (18.47–24.31)	21.56 (18.38–23.19)^b
Residual mass (kg)	13.88 (11.35–15.76)	13.81 (11.29–15.36)	14.96 (12.61–16.15)	15.01 (12.80–16.38)
Abdominal girth (cm)	92.00 (80.60–98.00)	92.00 (79.50–95.00)	96.00 (86.95–105.50)	101.5 (87.9–104.9)
Mid-thigh girth (cm)	51.3 (47.00–56.50)	52.4 (47.50–57.90)^a	52.10 (47.90–55.55)	52.2 (49.25–55.00)
Calf girth (cm)	35.20 (33.00–39.50)	36.00 (33.30–39.70)^a	35.20 (34.15–39.35)	35.30 (34.30–39.95)
Chalder Fatigue Scale	30.00 (24.00–35.00)	17.00 (14.00–24.00)^a	27.00 (23.50–34.00)	32.00 (23.50–36.50)^b
Muscular pain	6.00 (4.00–6.00)	3.00 (2.00–4.00)^a	5.00 (4.00–6.00)	5.00 (4.00–6.00)
Qualification of fatigue	5.00 (4.00–6.00)	2.00 (2.00–4.00)^a	5.00 (4.00–6.50)	5.00 (3.00–6.00)

Wilcoxon Test–scTox-Tr; baseline versus 3 months; statistical significance: p ≤ 0.05.

Wilcoxon Test–scTox-Sed; baseline versus 3 months; statistical significance: p ≤ 0.05.

scTox, subclinical thyrotoxicosis.

The impact of the exercise training and observation

After the follow up, patients with scTox-Tr had lower Σ9_SK (p = 0.01) and %BF (p = 0.02) than the baseline values. Patients with scTox-Tr also had higher muscle mass (p < 0.01), lean mass (p = 0.03), mid-thigh girth (p = 0.02), and calf girth (p = 0.03) (Table 2). The physical activity program did not influence the abdominal girth, the WRH, the bone mass, and the residual mass of the patients with scTox-Tr. Concerning fatigue, patients with scTox-Tr reduced the median values in Chalder Fatigue Scale (p < 0.01), muscular pain (p < 0.01), and fatigue qualification (p < 0.01). After 3 months of observation, patients with scTox-Sed had higher Σ9_SK (p = 0.05) and %BF (p = 0.05) and lower muscle mass (p = 0.04) than the baseline values. No differences were found with regard to abdominal girth, WHR, thigh girth, calf girth, bone mass, and residual mass in the patients with scTox-Sed (Table 2). Median Chalder Fatigue Scale score increased in patients with scTox-Sed (p = 0.03) in comparison to the baseline values, and no differences were found concerning muscular pain and fatigue qualification (Table 2).

Discussion

Since thyroid hormones are involved in many physiological functions of organisms such as the regulation of the resting metabolic rate, energy production, and muscle contraction (22,23), alterations in thyroid hormones production may influence body composition. Total weight loss is commonly observed in overt hyperthyroidism mainly due to progressive muscle mass weakness and atrophy (8,9), as well as decreased bone mineral density, which is associated with an increased risk of fracture and osteoporosis (10). These alterations, however, seem to be reversed after restoration to the euthyroid status. It is unclear whether patients with milder degrees of thyrotoxicosis are also affected in that way, particularly those on TSH-suppressive therapy with LT₄ for DTC. There is no consensus, because there are not enough studies, in particular prospective and randomized controlled trials; this makes disease management more difficult.

In the present randomized controlled trial that was not blinded, patients with scTox resulting from TSH-suppressive LT₄ therapy for DTC were evaluated for their body composition and fatigue perception and for how the systematic practice of physical activity affected these variables. One of the most notable results of our study was that the systematic practice of physical activity, twice a week for 3 months, was associated with an increase of about 9% (1.8 kg) in muscle mass and there was girth enlargement of lower limbs. At baseline, muscle mass was lower in the patients than in euthyroid control subjects as was mid-thigh girth as was commonly observed in overt thyrotoxicosis. Similar findings were reported by Brennan et al. (24) in 24 patients with subclinical hyperthyroidism caused by toxic nodular goiter or Graves' disease who had studies of their proximal thigh muscle size and strength. In them, measurements were performed at the beginning of the study and after the restoration of euthyroid status by thyroidectomy or radioactive iodine treatment. The authors concluded that both cross-sectional area and muscle strength were lower before the treatment than that of euthyroid controls and that there was improvement of these parameters after the restoration of euthyroid state. In another study performed by the same group of investigators, 21 patients with subclinical hyperthyroidism gained ∼2 kg in lean mass and increased their bone mineral density and thigh muscle cross-sectional area 6 months after thyroid status was restored to normal (25).

Muscle hypertrophy in response to exercise training occurs when an increase in the force of muscle contraction is required compared with that necessitated by everyday activities (26). In typical muscle growth, there is an increase in the number and the area of muscle fibers with a proportional increased DNA content. Satellite cells proliferate in response to the rupture of muscle fibers during training (27). Both aerobic and resistance training are associated with selective hypertrophy of muscle fibers but in a different manner. Aerobic stimulus is associated more with hypertrophy of type I fibers (slow twitch), and resistance training is associated more with hypertrophy of type II fibers (fast twitch). Biopsies of some muscles involved in the movement of running/walking demonstrate that vastus intermedius, gastrocnemius mediale, soleus, and tibiales anterior have a higher proportion of type I fibers; whereas vastus lateralis have a slightly higher proportion (by 58%) of type II fibers (28 –30). In this regard, we postulate that the increase of muscle mass observed in our study in patients who adhered to the physical activity program may have been due more to type I fiber hypertrophy since the training intervention was more an aerobic one. Besides, since all patients in the present study had been sedentary before the intervention and most of them were overweight, their training program may also have had a significant resistance component, which may also lead to type II fiber hypertrophy.

In the present study, patients with scTox and control subjects did not differ significantly with regard to body fat, evaluated by %BF and Σ9_SK. Nevertheless, the routine of physical activity reduced both variables in scTox-Tr. On the other hand, the scTox-Sed group had these parameters in greater degree.

Fatigue perception seems to be present in subclinical hyperthyroidism as it is in overt hyperthyroidism. Duyff et al. (31) evaluated the presence of neuromuscular signs and symptoms in 21 patients with newly diagnosed hyperthyroidism. They observed that 67% of the sample had complaints of weakness, muscle pain, cramps, or fatigability, confirmed by clinical testing. The authors thought that these complaints could be due to a functional muscle disorder, as they were resolved during treatment when an overall increase of muscle strength in patients was observed. A study performed with 20 patients with subclinical hyperthyroid randomly divided into two groups showed that fatigue was present in 90% of patients before therapy and in 40% of patients before observation without any treatment. After the restoration of euthyroid status, complaints of fatigue diminished to 40%, whereas it was increased to 60% among patients without treatment (32). In contrast, Gulseren et al. (33) reported that sweating and palpitation were the most frequent complaints related by patients with subclinical hyperthyroidism; pain in the extremities associated with fatigue was a lesser symptom (23%).

This study demonstrated that physical activity may be an important strategy to be adopted in the management of fatigue symptoms in exogenous subclinical hyperthyroidism. This was observed, as patients who adhered to the exercise training have their fatigue complaints substantially reduced. Moreover, those ones that remained inactive during the 3 months of observation had their complaints increased.

In conclusion, our results suggest that exogenous scTox caused by TSH-suppressive therapy with LT₄ for DTC is associated with alterations in muscle mass, mid-thigh girth, and fatigue. The practice of physical activity, specifically aerobic training, twice a week, during 3 months, however, partially reversed these signals and symptoms in the sample studied, principally in relation to fatigue. Further studies are required to determine the optimum amount and type of exercise that should be encouraged in patients with scTox due to TSH suppressive therapy with LT₄. In designing these studies, both beneficial and adverse responses should be considered.

Footnotes

Acknowledgments

National Council of Technological and Scientific Development (CNPq); José Bonifácio University Foundation (FUJB); Carlos Chagas Filho Foundation (FAPERJ); and Leonardo Vieira Neto.

Disclosure Statement

The authors declare that no competing financial interests exist.

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