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

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Neuromuscular symptoms and impaired muscle energy metabolism have been described in subclinical hypothyroidism (sHT). 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-T(4) replacement in a double-blind, randomized, placebo-controlled fashion. We studied 23 sHT patients and 10 matched euthyroid controls. Oxygen uptake (VO(2)), carbon dioxide output, and heart rate were measured during incremental step-up exercise. Blood glucose, lactate, pyruvate, free fatty acid, glycerol, and beta-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-T(4)-restored euthyroidism. Maximal power output (P = 0.02) and VO(2) max (P = 0.04) were reduced in sHT, and, with increasing workload, patients achieved higher heart rates (P < 0.03) at VO(2) 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-T(4) replacement, while improving neuromuscular symptoms, did not produce significant changes in the energy or substrate response to exercise. 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.
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... Untreated overt and subclinical hypothyroidism was associated with two-fold higher prevalence of depression compared with normal control [20,21]. Fatigue and impaired exercise tolerance are proven consequences of subclinical hypothyroidism [13,22]. Anxiety and disability scores assessed by Hamilton anxiety rating scale and brief disability questionnaire are higher in overt hypothyroidism compared with healthy controls [19]. ...
... Some studies were prospective, blinded, and placebo controlled, whereas others were cross-sectional cohorts like this study. Finally, few studies included one-fifth to one-third of their patient not achieving euthyroidism at the time of evaluation [4][5][6][7][8][9][10][11][12][13][14]19,20,[22][23][24][25][26][27]. ...
... The second important finding in this study is a better score on impaired daily life scale. Unlike this study findings, euthyroidism for variable durations was associated with nonimprovement in tiredness, fatigue, exercise tolerance, and physical domains of QoL [10,11,22,[25][26][27]. However, other studies reported an improvement in fatigue, frequency of tiredness, and physical/somatic aspects of QoL [5,6,8,13,23]. ...
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Background Levothyroxine is the recommended treatment to achieve euthyroidism in hypothyroid patients. Achieving euthyroidism was found to improve quality of life in some studies but failed to do so in other studies. Thyroid patient reported outcomes (ThyPRO) is a thyroid-specific health-related quality of life measure. This study aims to assess patient-reported outcomes in levothyroxine-treated hypothyroid patients using ThyPRO. Patients and methods The study included 194 patients, divided into two groups: group 1 included 141 hypothyroid patients with benign thyroid disease treated with l-thyroxine, stable in euthyroidism for at least 6 months, and group 2 included 53 patients with euthyroid benign thyroid disease. All patients completed a professionally translated, carefully revised version of the ThyPRO questionnaire into Arabic language. All patients had theirThyroidstimulatinghormone(TSH) measuredatinclusion.Anti-thyroperoxidase and/or anti-thyroglobulin antibodies were recorded for each patient where available. Results There were no significant differences between the two studied groups regarding age, sex, and TSH. Anti-thyroperoxidase antibodies were significantly higher in treatment group versus group 2, but anti-thyroglobulin antibodies did not differ among the two studied groups. Group 1, l-thyroxine treatment group, showed significantly lower scores in the goiter symptoms, depressivity, impaired daily life, and hyperthyroid symptom scales compared with group 2. No significant differences were found regarding the remaining symptom scales. Conclusion Hypothyroid patients of different etiologies rendered euthyroid for at least 6 months compared with euthyroid patients with benign thyroid disease have significantly better depression, goiter, impaired daily life scores using a thyroid-specific questionnaire, the ThyPRO, compared with euthyroid benign thyroid disease. Keywords: depressivity, goiter symptoms, hypothyroidism, impaired daily life, levothyroxine
... Although moderate and often insignificant elevations of muscle enzymes (CPK and LDH) are common during SCH [32][33][34], the symptomatic muscle impact of these endocrinopathy remains exceptional. Myopathy can result in myalgia or muscle stiffness but mainly it is intolerance to exercise as evidenced by hyperlactatemia, reduced oxygen consumption (VO2max), and increase in respiratory coefficient during exercise [35] as well as abnormally high intramuscular acidification at the end of exercise detected by phosphorus magnetic resonance spectrometry [36]. ...
... The electromyogram (EMG) remains conventionally unchanged during SCH [35] but a significant increase in repetitive discharges both at rest and after physical exercise or during ischemia can be detected by surface EMGs. These anomalies are the translation of a neuromuscular hyper-excitability which could result from a tendency to decrease of the extra cellular ionized calcium which characterizes SCH [37,38]. ...
... 1-Lipids and Cardiovascular Disease (CVD) in SCH: Screening for hypothyroidism is usually done when evaluating secondary causes for abnormal lipid profile especially elevated low-density lipoprotein cholesterol (LDL-C) and triglyceride levels (18). Various reports linked hyperlipidemia and early CVD to SCH, specifically, increased levels of total cholesterol (TC) and LDL-C in SCH patients compared to controls (19). Hyperlipidemia tends to be worse in patients with higher TSH concentrations or in patients with elevated LDL-C at baseline (20). ...
... LT4 replacement therapy vs. no treatment has been shown to improve cardiopulmonary performance (O 2 uptake, minute ventilation, and heart rate) in subjects with subclinical hypothyroidism [32], although not all studies have shown this [33]. In another study, variation of LT4 doses to induce minor fluctuations of TSH around the reference range did not influence energy expenditure or body composition in patients with hypothyroidism [34]. ...
... Nonetheless, there appeared to be a small increase in the prevalence of iodine deficiency over this period in the Americas (54) . Like iron deficiency, low iodine levels are of particular concern in military SM because of detrimental effects on muscle function and exercise capacity (55) and adverse effects on work capacity (56) . Data in the present study suggest that iodine disorder rates are rising in military men but less so in military women. ...
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Objective Iron and/or iodine deficiencies can have multiple serious adverse health outcomes, but examination of incidence rates of these deficiencies have rarely been conducted in any large population. This study examined incidence rates, temporal trends, and demographic factors associated with medically-diagnosed iron and iodine deficiencies/disorders in United States (US) military service members (SMs). Design The Defense Medical Epidemiological Database (DMED) was queried for medical visits of active duty SMs to obtain specific International Classification of Diseases, Version 9, codes involving clinically-diagnosed iron and iodine deficiencies/disorders. Setting Analysis of existing database (DMED). Participants Entire population of US military service members from 1997 to 2015 (average N per yr=1,382,266, 15% women). Results Overall incidence rates for iron and iodine were 104 and 36 cases/100,000 person-years, respectively. Over the 19-year period, rates for iron disorders increased steadily (108% for men, 177% for women). Rates for iodine disorders also increased steadily for men (91%), but for women there was an initial rise followed by a later decline. Overall, women’s rates were 12 and 10 times higher than men’s for iron and iodine, respectively. Compared to whites, blacks and those of other races had higher rates of deficiencies of both minerals. Incidence rates for iodine deficiency increased substantially with age. Conclusion The overall incidence of clinically-diagnosed iron and iodine deficiency among SMs was low, but increased over the 19 years examined and certain demographic groups were at significantly greater risk. Given the unexpected increases in incidence of these mineral disorders increased surveillance may be appropriate.
... [27][28][29][30] The impairment of cardiopulmonary function may be considered as the indication for initiation of L-thyroxine at the subclinical stage of hypothyroidism. [31][32][33] Hence, the present study was aimed to assess the cardiopulmonary fitness by Queens College step tests in patients of SCH to find out impairment if any. ...
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Background: Subclinical Hypothyroidism (SCH) represents the earliest stage of hypothyroidism. SCH is defined biochemically as a high serum thyroid-stimulating hormone (TSH) and normal serum free thyroxine (fT4) and triiodothyronine (fT3) concentrations. Cardiopulmonary fitness reflects the overall capacity of the cardiovascular and respiratory system. VO2 max, also known as maximal oxygen uptake, is the measurement of the maximum amount of oxygen a person can utilize during intense exercise. Objective: The aim of this prospective observational case-control study was to evaluate the cardiopulmonary fitness of patients diagnosed with SCH. Methods: The study comprised of 140 participants (80 patients with SCH and 60 healthy controls) in the age-group of 18-55 years. VO2 max was estimated indirectly by following the protocol of Queen's College Step Test (QCT) method to assess cardiopulmonary fitness Results: The patients of SCH and Controls were comparable for age, gender, weight, waist circumference, BMI and hemodynamic parameters. TSH was significantly elevated in SCH than controls while fT4 and fT3 were comparable. The patients of SCH showed a significant reduction VO2 max as compared to controls 46.4±8.6 and 49.8±9.8 ml/kg/min respectively (P=0.029). VO2 max was significantly reduced in female SCH than male SCH (P=0.001). Conclusion: Cardiopulmonary functions were affected in patients with SCH. A mild cardiopulmonary dysfunction was seen in patients with SCH particularly in females.
... Metabolic issues arising from HT stem from reduced transcription of thyroid hormone gene targets related to glucose uptake, ATP production, and mitochondrial efficiency (Amati et al. 2009;Maratou et al. 2009;Salvatore et al. 2014;Sindoni et al. 2016). Both glycolytic and oxidative energy pathways become impaired leading to reliance on muscle glycogen, excessive lactate production and reduced fatty acid oxidation (Caraccio et al. 2005;McAllister, Delp, and Laughlin 1995;Monzani et al. 1997). Further, inflammatory markers like excessively high serum creatine kinase (CK) levels, elevated myoglobin, IL-6, and reactive oxygen species have been detected in SKM of individuals with HT 1 37 8 4 6 18 2 68 21 7 9 37 3 97 13 5 19 37 4 55 8 1 6 15 5 39 4 2 6 12 6 18 2 0 1 3 7 10 4 0 2 6 Total 324 60 19 49 128 CV = aerobic/cardiovascular exercise, RT = resistance training, CVRT = combination of both aerobic/ cardiovascular and resistance training. ...
Article
This study examined the effect of exercise on skeletal muscle symptoms experienced by women with hypothyroidism. An online survey on exercise participation was completed by female participants undergoing treatment for hypothyroidism (n = 580). Basal muscle symptoms (MS) and exercise muscle symptoms were analyzed by the type of exercise performed, cardiovascular/aerobic (CV), resistance training (RT), or both (CVRT). Exercise participation affected MS (F = 7.186, p < .01) with respondents performing a combination of CVRT reporting the lowest basal MS compared to those performing CV (p = .044), RT (p = .031) alone, or those performing no exercise at all (p < .001). Associations between muscle pain (χ² = 7.963, p = .019) and muscle fatigue (χ² = 14.240, p < .001) during exercise and by exercise type were found. Muscle pain during exercise was also associated with an exercise type and frequency (χ² = 24.164, p < .019). Finally, there was an association between recovery from exercise and frequency of exercise bouts (χ² = 32.185, p < .001). Women with hypothyroidism commonly experience skeletal muscle symptoms at rest and during exercise. The results from this study indicate the type of exercise performed may have an impact on the occurrence of these symptoms.
... An earlier study reported that TSH was the dominating lipolytic hormone in vitro during the neonatal period, when serum TSH levels surge dramatically 29 . FFAs have been found previously to be higher in SCH patients and the higher blood glycerol levels observed suggested that this increase in circulating FFAs was, at least in part, caused by enhanced lipolysis 17 . Similarly, another study showed that TSH raised serum FFA levels in vivo by stimulating adipocyte lipolysis, managed by phosphorylation of perilipin and hormone-sensitive lipase in a protein kinase A-dependent manner in differentiated adipocytes 30 . ...
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Subclinical hypothyroidism (SCH) is a common endocrine disorder affecting women of reproductive age. Although SCH and abnormal fatty acid composition are often associated with adverse pregnancy outcomes and metabolic syndrome later in maternal and fetal life, the longitudinal relationship between SCH and serum fatty acids during pregnancy has rarely been studied. Therefore, the aim of this study was to investigate the association between SCH and maternal serum fatty acids throughout gestation. A total of 240 women enrolled in the Complex Lipids in Mothers and Babies (CLIMB) study in Chongqing, China were included in our study. Clinical information and maternal serum samples were collected at three time points during pregnancy: 11–14th, 22–28th, and 32–34th weeks of gestation. Twenty serum fatty acids were quantified using gas chromatography-mass spectrometry (GC-MS) analysis. A majority of the 20 serum fatty acids increased as gestation progressed in women with a normal pregnancy and women experiencing SCH. Levels of arachidic acid, docosahexaenoic acid, and eicosenoic acid were significantly higher in the serum of women with SCH when compared to women with a normal pregnancy, in the second trimester. On the other hand, the levels of eicosadienoic acid and octadecanoic acid were significantly higher in SCH in the third trimester. Our findings demonstrate that serum fatty acid composition during the second and third trimesters was significantly associated with SCH in pregnant Chinese women.
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Objectives Dysphonia is a common compliant in hypothyroid patients. Subjective voice changes could be clearly found in congenital hypothyroid children (CHC); however, the early treated children with thyroid hormone replacement (THR) may not experience dysphonia. The objective of this study is to determine if the CHC who were receiving early THR would have objectively measurable changes on vocal function as assessed by the dysphonia severity index (DSI). Methods Participants were 29 children aged from 6 to 12 years. Fifteen children had congenital hypothyroidism on eltroxin therapy started before the age of 1 year and 14 were typically developing children (TDC). All children did not have voice compliant. DSI was calculated for all children through the measure of maximum phonation time (MPT), highest frequency (F 0 -high), lowest intensity (I-low), and jitter percent (j %). Results CHC receiving early THR were not significantly different from TDC on DSI value; however, both groups showed significant difference on MPT and F 0 -high. Degree of voice changes by DSI in males was significantly higher than females in CHC on eltroxin therapy while no significant difference regarding gender has been found on DSI in TDC. Conclusions The results suggested that there is no evidence of DSI objective voice changes in CHC receiving THR compared to TDC, yet separate objective voice measures alternations had been found in CHC. This highlights the importance of achieving efficient neonatal screening programs for CHC and providing strong support to initiate early THR to avoid any alternation of laryngeal function.
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