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Muscle Metabolism and Exercise Tolerance in Subclinical Hypothyroidism: A Controlled Trial of Levothyroxine

Department of Internal Medicine, and Consiglio Nazionale delle Ricerche Institute of Clinical Physiology, University of Pisa School of Medicine, 56126 Pisa, Italy

Address all correspondence and requests for reprints to: Ele Ferrannini, M.D., Department of Internal Medicine, University of Pisa, Via Roma 67, 56126 Pisa, Italy. E-mail: ferranni{at}ifc.cnr.it.

	Abstract

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Background: Neuromuscular symptoms and impaired muscle energy metabolism have been described in subclinical hypothyroidism (sHT).

Aim: The aim of the study was to evaluate the energy and substrate response to exercise in sHT patients using a standardized protocol and to test the effect of L-T₄ replacement in a double-blind, randomized, placebo-controlled fashion.

Patients and Methods: We studied 23 sHT patients and 10 matched euthyroid controls. Oxygen uptake (VO₂), carbon dioxide output, and heart rate were measured during incremental step-up exercise. Blood glucose, lactate, pyruvate, free fatty acid, glycerol, and ß-hydroxybutyrate concentrations were measured at rest, every 2 min during exercise, and during 20 min of recovery. The exercise protocol was repeated after 6 months of placebo or L-T₄-restored euthyroidism.

Results: Maximal power output (P = 0.02) and VO₂ max (P = 0.04) were reduced in sHT, and, with increasing workload, patients achieved higher heart rates (P < 0.03) at VO₂ values equivalent to those of controls. The respiratory quotient increments were significantly higher in patients than controls (P < 0.04). Blood lactate and pyruvate and their ratio rose with a steeper slope (P < 0.0001, P < 0.001, and P < 0.01, respectively) in patients than controls. Resting plasma free fatty acid and blood glycerol levels were significantly higher in patients than controls (P < 0.0003 and P < 0.003, respectively) throughout baseline, exercise, and recovery. L-T₄ replacement, while improving neuromuscular symptoms, did not produce significant changes in the energy or substrate response to exercise.

Conclusions: The response to exercise is altered both in terms of tolerance and pattern of substrate utilization in sHT patients. Restoring stable euthyroidism does not correct this defect over a 1-yr period.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
SKELETAL MUSCLE IS a target organ for thyroid hormones (1), and neuromuscular deficits are well-established findings in hypothyroidism (2). Biochemical abnormalities such as glycogen accumulation and decreased activity of enzymes involved in energy production have been described in hypothyroid type I muscle fibers (3, 4, 5). The presence of T₃ receptors on the mitochondrial membrane in skeletal muscle suggests a direct effect of thyroid hormones on oxidative metabolism (6). A degree of mitochondrial impairment in hypothyroidism is suggested by the reduced activity of key mitochondrial enzymes and electron transport chain cytochrome complexes (7, 8, 9). In two studies using phosphorus nuclear magnetic resonance (1, 10), the rapid decline in energy reserves of exercising hypothyroid muscle was attributed to reduced mitochondrial activity. Another study using the same technique, however, proposed a defect in glycogen breakdown as the mechanism (11). Thus, the metabolic consequences of hypothyroidism in skeletal muscle are still controversial.

Subclinical hypothyroidism (sHT) is defined by an isolated elevation in circulating TSH levels in the face of normal free thyroid hormone concentrations (12). Several studies have reported that sHT may be associated with metabolic, cardiovascular, and neuromuscular features similar to those observed in frank hypothyroidism (13, 14, 15). Previous work from our laboratory has documented an impairment of muscle energy metabolism in sHT patients during incremental, submaximal exercise leading to an excessive lactate production; a defective mitochondrial function was postulated as the pathogenic factor (16).

The aim of the present study was to measure the energy and metabolic response to a standardized bout of physical exercise in patients with sHT and the effect on this response of 12 months of levothyroxine (L-T₄) replacement in a double-blind, randomized, placebo-controlled fashion.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patients

Twenty-three sHT patients, recruited from the outpatient clinic, participated in the study (Table 1). All patients were characterized by elevated serum TSH levels (>3.6 mIU/liter) and free thyroid hormone (FT₄ and FT₃) levels within the normal range. All patients suffered from Hashimoto’s thyroiditis and had positive antithyroid peroxidase (TPOAb) and antithyroglobulin (TgAb) autoantibody titers. The control group included 10 healthy subjects, matched to the patients for sex, age, body mass index (BMI), and body composition, who were recruited among hospital staff and relatives of patients. Before entry into the study, a blood sample for TSH, FT₄, FT₃, TgAb, and TPOAb determination and routine laboratory chemistry was taken at 0800 h after an overnight fast. Neurological, cardiovascular, respiratory, and other systemic diseases were excluded in patients and controls by a complete clinical work-up; no study subject assumed any drugs. Neither patients nor controls were physically trained in the sense of participating in structured training programs or agonistic activities. An expert physician, who was not aware of their hormonal status, administered a simple questionnaire on neuromuscular symptoms to all study subjects. The questionnaire asked whether any of four symptoms (paresthesias, muscle cramps, fatigue, and muscle weakness) had occurred at least once over the previous 30 d.

Exercise protocol

The day before the exercise test, a 2-h, 75-g oral glucose tolerance test (OGTT) was performed in all study subjects for the determination of plasma glucose and insulin concentrations. An entry criterion for both sHT patients and controls was that they had normal glucose tolerance (i.e. a fasting plasma glucose <7 mmol/liter and a 2-h glucose level <7.8 mmol/liter). For the exercise test, subjects were instructed to avoid physical exertion during the 48 h preceding the test session and to arrive at the research center in a rested and fully hydrated state. The test was performed at 0800 h after an overnight fast, in a quiet, air-conditioned room (22–24 C), with the subjects wearing lightweight running clothes and running shoes. The test took place at the same time of day to minimize the effect of circadian rhythms. Before the exercise session, subjects had an indwelling venous catheter placed in the antecubital vein and were accustomed to the procedure by 3 min of low-intensity exercise, after which they sat quietly for 20 min. The test was performed on a bicycle ergometer (2400 Siemens) with subjects breathing through a mouthpiece with a one-way valve for exhaled gas collection. Seat and handlebar positions on the bicycle were adjusted to each subject’s comfort and maintained in that position for the subsequent exercise test. The exercise protocol consisted of 4 min of unloaded cycling followed by step increments of workload of 10 W·min^–1 in women and 15 W·min^–1 in men every 2 min. Both patients and controls were instructed to maintain a pedaling rate of 70 rpm. Subjects were given verbal encouragement throughout the test, which was interrupted when subjects could no longer maintain the desired pedaling rate and/or felt exhausted. Breath-to-breath oxygen uptake (VO₂), carbon dioxide output, and minute ventilation were measured with the use of a computer-based system (Metabolic Measurement Cart/System 2900n; Sensor Medics, Yorba Linda, CA), and averaged over 60-sec intervals. VO₂ and carbon dioxide output were normalized to the subject’s lean body mass, and expressed as ml·min^–1·kg^–1. Before each exercise test, the O₂ and CO₂ analyzers were calibrated using gaseous standards of known concentration with an error of 0.01%. The flow sensor was calibrated by flushing air from a 3-liter syringe at varying flows and frequencies.

Blood samples were obtained at rest (immediately after the warm-up), at the end of each step of the ramp, and every 2 min during recovery for the measurement of glucose, lactate, pyruvate, free fatty acids (FFA), glycerol, and ß-hydroxybutyrate. The exercise protocol was repeated after 6 months of placebo therapy or 6 and 12 months of restored euthyroidism with L-T₄ therapy. Patients were randomly assigned to receive either L-T₄ (Eutirox; Bracco S.p.A., Milan, Italy) replacement therapy (n = 12), 25 µg twice daily, or two identical placebo tablets (n = 11) in a blinded manner. All patients returned after 3 months for repeat thyroid function tests. One of us (N.C.) had access to the treatment code and increased the L-T₄ dose by 25 µg if the TSH level was still higher than 3.6 mIU/liter. Titration continued until euthyroidism was reached; the mean final replacement dose of L-T₄ was 65 µg daily. Patients taking placebo completed an identical protocol, some of them being given additional placebo tablets to maintain the blindness of the study. Six months after the serum TSH level had become normal (in the L-T₄-treated patients) or 6 months and 1 yr after the final dosage was assigned (in the placebo-treated patients), the patients were readmitted to the Clinical Research Center for repeat OGTT and complete exercise protocol. After completion of this second set of studies, the patient code was broken, and the patients on placebo were put on L-T₄ therapy. The patients already on L-T₄ therapy were maintained on it, and 11 of them returned 6 months later for repeat OGTT and exercise protocol.

Analytical measurements

Serum FT₃ and FT₄ levels were measured by specific RIA (Techno-Genetics Recordati, Milan, Italy). TSH was determined with an ultrasensitive immunoradiometric assay (IRMA) method (Cis Diagnostici, Tronzano Vercellese, Italy). TgAb were measured by a specific IRMA (TG-Ab IRMA; Biocode, Sclessin, Belgium); TPOAb were measured by a specific RIA (AB-TPO; Sorin Biomedica, Saluggia, Italy). Insulin was assayed by a specific RIA (LINCO Research, Inc., St. Charles, MO). Plasma glucose was measured on an automatic analyzer, Hitachi 717 (Boehringer Mannheim, Mannheim, Germany); plasma FFA were measured spectrophotometrically (Wako, Neuss, Germany). Whole-blood lactate, pyruvate, glycerol, and ß-hydroxybutyrate levels were determined spectrophotometrically on an ERIS analyzer 6170 (Eppendorf Garatebau, Hamburg, Germany). For the latter assays, blood samples were collected into iced tubes containing 1 M perchloric acid for immediate deproteinization; the supernatant obtained from centrifugation was stored at –20 C and assayed within 30 d. Normal values in our laboratory are as follows: FT₄, 6.8–20 pmol/liter; FT₃, 4.3–8.6 pmol/liter; TSH, 0.30–3.6 mIU/liter; Tg-Ab, less than 50 IU/ml; and TPO-Ab, less than 10 IU/ml.

Statistical analysis

Data are expressed as the mean ± SEM. Areas under time-concentration curves (AUC) were calculated by the trapezium rule. Group comparisons were performed using ANOVA for independent samples. ANOVA for repeated measures was used to test for group differences in the response to exercise.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Baseline studies

At baseline, serum TSH levels were significantly higher in sHT patients than controls, whereas free thyroid hormone concentrations were not significantly different. Glucose tolerance and the insulin response to oral glucose (as the respective AUC) did not differ between the two groups. No differences were observed in resting VO₂ rates or the respiratory quotient (RQ) (Table 1).

The response to exercise was significantly impaired in sHT patients. In terms of exercise tolerance, both maximal power output (79 ± 6 vs. 114 ± 17 W; P = 0.02) and maximal VO₂ (38.0 ± 1.0 vs. 42.4 ± 2.1 ml·min^–1·kg^–1; P = 0.04) were lower in the patients. With increasing workload, patients achieved higher heart rates (P < 0.03 for the first five steps, completed by all patients) at equivalent VO₂ rates as those of the controls. The RQ rose during exercise (P < 0.0001); this change was significantly greater in patients than controls (P < 0.04) (Fig. 1).

View larger version (20K): [in this window] [in a new window]   FIG. 1. Time course of heart rate, VO2 (in ml·min–1·kg–1 of lean body mass), and RQ in patients with sHT and euthyroid control subjects. All sHT patients completed the fifth step (10 min), 19 completed the sixth, 13 completed the seventh, 11 completed the eighth, eight completed the ninth, five completed the 10th, and only one completed the 11th. During recovery, all study subjects are represented at equivalent times (ergo, the break in the time scale between stepped exercise and recovery).

View larger version (22K): [in this window] [in a new window]   FIG. 2. Time course of blood lactate and pyruvate concentrations, and their ratio, in patients and controls during stepped exercise and recovery.

View larger version (19K): [in this window] [in a new window]   FIG. 3. Blood lactate concentrations in relation to VO2 (in ml·min–1·kg–1 of lean body mass).

View larger version (24K): [in this window] [in a new window]   FIG. 4. Time course of plasma FFA, blood glycerol, and ß-hydroxybutyrate concentrations in patients and controls during stepped exercise and recovery.

The baseline characteristics of the sHT patients randomized to placebo or L-T₄ replacement therapy were similar. After 6 months of stable euthyroidism, serum TSH levels in L-T₄-treated patients were normalized and no longer different from those of control subjects, whereas they were unchanged in placebo-treated patients (Table 2). However, in L-T₄-treated patients, none of the measured parameters (glucose tolerance, insulin response to glucose, resting heart rate, resting and maximal VO₂, and maximal power output) changed significantly, either with respect to baseline or in comparison with the corresponding changes observed in the placebo group. Likewise, changes in heart rate, VO₂, and blood metabolites during exercise and recovery showed no significant differences between placebo and active treatment. The 11 patients maintained on active treatment until 1 yr failed to show any consistent change from the preceding treatment period or from baseline (Fig. 5).

View larger version (17K): [in this window] [in a new window]   FIG. 5. Blood lactate, lactate/pyruvate ratio, and plasma FFA concentrations (expressed as AUC) in placebo- or L-T4-treated patients at baseline and follow-up. Note that placebo-treated patients were not restudied at 1 yr.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
We have previously described elevated blood lactate levels in sHT patients during incremental, submaximal forearm exercise (16) and have postulated a defect in mitochondrial function as the pathogenetic mechanism. To confirm and extend these findings, in the present group of patients, we measured the energy and substrate response to exercise using a standardized protocol. It is important to emphasize that we selected sHT patients with rigorously normal glucose tolerance and matched them to euthyroid subjects with very similar anthropometric and clinical characteristics to rule out biases caused by differences in age, obesity, or glucose tolerance. In addition, we made an effort to also match patients and controls by reported physical activity, although the latter is known to be a relatively poor indicator of physical fitness.

Changes in cardiac function indices have been reported in sHT patients (17, 18). In a comprehensive study of exercise capacity, sHT was found to be associated with impairment of several exercise-related cardiopulmonary responses, resulting in some degree of exercise intolerance (19). In particular, cardiovascular function and work capacity was assessed by stress echocardiography and respiratory gas analysis on a ramp-loading cycle ergometer. Although the regression of heart rate on VO₂ showed a reduced slope in comparison with controls, in sHT patients the oxygen pulse (VO₂ per heart beat), an index of stroke volume, was significantly reduced either at the anaerobic threshold or at a maximal workload (19). Therefore, abnormal cardiovascular function contributed to the reduced work capacity in sHT patients.

In accord with these findings, in our sHT patients the response to exercise was impaired and was not corrected by L-T₄ replacement to a significant extent over the period of time of the trial. With regard to the pattern of substrate use, in the euthyroid controls, stepped exercise was associated with the expected rise in circulating lactate and pyruvate concentrations and a moderate rise in their ratio. This result indicates that with increasing work rate the availability of glucose, from enhanced liver production as well as from glycogen stores, exceeded the ability of body tissues to oxidize it, resulting in lactate and pyruvate regurgitation into the bloodstream and a fall in intracellular pH. The observed increase in the RQ marks the preference given to carbohydrate over fat oxidation, which develops as the increasing workload mounts an oxygen debt. In line with these physiological responses is also the increase in lipolysis, signaled by the rising blood glycerol levels, activated by the adrenergic response to exercise. The fall in circulating FFA levels indicates that the increased energy demand is also met by fat oxidation, which is stimulated in excess of lipolysis (20, 21). In sHT patients, the increase in VO₂ at each given level of work was very similar to that of controls, suggesting that work efficiency was normal at least up to their tolerance threshold. However, heart rate was higher than in controls at each level of VO₂, indicating a reduced cellular oxygen extraction. The substrate response to exercise was fully compatible with their reduced ability to use oxygen. The exaggerated rise in blood lactate and pyruvate levels, and in their ratio, is the expected consequence of such impaired oxygen use (21).

The pattern of circulating fatty substrates differed from that of controls not so much in response to the exercise protocol but in the resting state. In sHT patients, FFA were higher throughout the protocol, and the higher blood glycerol levels suggested that this increase in circulating FFA was, at least in part, caused by enhanced lipolysis. The raised ketone levels indicated increased hepatic FFA oxidation; the greater rise in RQ indicates a relative inability to oxidize fat. In previous studies in animal models of hypothyroidism or in vitro systems, lipolysis has been found to be reduced (22). This notion, however, is not supported by studies in overtly hypothyroid humans, in whom rates of FFA turnover were normal (23), and has never been tested in sHT. Moreover, sHT is associated with increased levels of circulating catecholamines, possibly as a result of enhanced production (18, 24). An increased sympathetic activity may help explain the heart rate changes during exercise and the enhanced lipolysis observed in our patients. Lastly, if glucose use in fat cells were impaired, this would result in unrestrained lipolysis with the full set of metabolic consequences observed in our patients: increased delivery of FFA to the liver and increased hepatic FFA oxidation with enhanced ketone production. Indeed, in fat cells obtained from hypothyroid subjects, Pedersen et al. (25) found that both glucose transport and lipogenesis were impaired, to an extent that was conspicuously similar to that seen in adipocytes from hyperthyroid subjects. Furthermore, Matsuoka et al. (26) reported in vivo insulin resistance in a few patients with hypothyroidism, which was not reversed by normalization of thyroid function. Additional studies are needed to confirm this observation.

The possibility that a mitochondrial defect may contribute to the impaired oxygen use seen in sHT patients must be considered. A muscle mitochondrial defect (1, 10, 16), together with the known structural alterations of skeletal muscle, more pronounced in frank hypothyroidism (4, 11) but also present in sHT (20, 27), may underlie the muscular symptoms frequently reported by sHT patients. In turn, the neuromuscular deficit may account, at least in part, for the reduced physical fitness. In the present trial, successful L-T₄ replacement therapy was associated with a clear improvement of the subjective symptoms but was insufficient, at least within 1 yr, to also normalize exercise tolerance and the metabolic response to exercise. It remains to be proven whether more prolonged euthyroidism may eventually restore fitness and adipose tissue insulin sensitivity.

	Acknowledgments

 
We thank Sara Burchielli for her assistance.

	Footnotes

 
This work was partly supported by grants from Ministero Istruzione, Università e Ricerca, Rome, and Bracco S.p.A., Milan, Italy.

First Published Online April 26, 2005.

Abbreviations: AUC, Area under the curve; BMI, body mass index; FFA, free fatty acids; FT₄, free T₄; IRMA, immunoradiometric assay; L-T₄, levothyroxine; OGTT, oral glucose tolerance test; RQ, respiratory quotient; sHT, subclinical hypothyroidism; TgAb, antithyroglobulin antibody; TPOAb, antithyroid peroxidase antibody; VO₂, oxygen uptake.

Received December 1, 2004.

Accepted April 18, 2005.

	References

Top Abstract Introduction Patients and Methods Results Discussion References

 

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This Article Abstract Full Text (PDF) All Versions of this Article: 90/7/4057    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Caraccio, N. Articles by Ferrannini, E. Search for Related Content PubMed PubMed Citation Articles by Caraccio, N. Articles by Ferrannini, E. Related Collections Metabolism Thyroid