Effect of physical exercise in people with hypothyroidism: systematic review and meta-analysis

Abstract This study aimed to systematically revise the available evidence on the effects of physical exercise training programmes on people with hypothyroidism. Comparative studies were searched in six electronic databases until April 2023. The Physiotherapy Evidence Database and the Methodological Index for Non-Randomized Studies were used to determine the methodological quality of the randomized controlled trials and comparative studies respectively. A total of 10 studies were found showing a low to moderate methodological quality. Most of them were performed in women with subclinical hypothyroidism. Exercise seemed to be safe, with aerobic and resistance training leading to improvements in outcomes related to physical and mental health. The performed meta-analysis with data from 120 participants indicated that exercise showed a non-significant trend towards reducing thyroid-stimulating hormone levels (Hedges’g −0.96; 95% CI −2.71; 0.79, p = 0.160; I2 = 92%). When the analysis was performed by comparing the experimental, and control groups with data from 180 participants the results remained non-significant (SMD −1.09; CI 95% −2.88; 0.70, p = 0.23; I2 = 95%). Similar findings were obtained when pooling data for FT3 and FT4 levels. Exercise does not have a significant impact on thyroid function, although its practice can lead to secondary outcomes related to physical and mental health.


Introduction
Hypothyroidism (HT) is a condition characterized by deficient production of thyroid hormone due to either an existent abnormality in the thyroid gland (primary HT) or as a result of hypothalamic or pituitary disease (secondary or central HT).Primary HT is widely prevalent worldwide and it usually can be categorized according to its severity as subclinical (SCH) or overt (OVH) [1].In the case of SCH, there is an elevated thyroid-stimulating hormone (TSH) concentration due to the presence of low but within range values of serum free thyroxine (FT4) levels.In contrast, OVH is characterized by elevated TSH in combination with circulating levels of FT4 that are below the lower limit of the reference range [2].
Thyroid hormone replacement therapy is the mainstay of management for individuals with HT.This treatment generally results in resolution of the signs and symptoms related to the pathology, although not all patients feel that this pharmaceutical approach is efficacious in restoring optimal health [3].Indeed, it has been stated that approximately 10% to 15% of patients with HT following replacement therapy continue to experience impaired quality of life, persistent fatigue, physical constraints and exercise intolerance, which all together can lead to an inability to perform physical activity [4].This is a matter of concern, since leading a sedentary lifestyle could increase the risk of non-communicable diseases such as coronary heart disease, heart failure, cerebrovascular disease, hypercholesterolemia atherosclerosis or hyperlipidemia, which have been associated with primary HT [5][6][7].It should also be noted that an increase in the risk of cardiovascular disease and mortality has been observed in people with SCH [8].
In accordance with all this, encouraging people with HT to exercise seems to be imperative, given that its practice its associated with positive changes in the aforementioned cardiovascular and metabolic pathologies.However, the development of global recommendations towards exercise practice in people with HT seems a complex challenge.On one hand, the presence of exercise intolerance poses a challenge to recommending it.On the other hand, the existing body of knowledge concerning the effects of exercise training programs in this population is limited [9].
Consequently, before providing counselling on physical exercise to people with HT, endocrinologists, general practitioners, and sports physicians need to be provided with the most accurate evidence-based guidelines currently available for its prescription and its potential benefits within this population.To the very best of the authors' knowledge, only one systematic review has addressed the efficacy of exercise on people with HT [9].However, no firm conclusions could be drawn due to the reduced number of studies found.Thus, an updated overview seems necessary.In the light of all this, this systematic review aims to gather scientific evidence on the effects of physical exercise training programmes on people with HT.

Design
This systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [10].The study protocol was registered in Open Science Framework (OSF)https://doi.org/10.17605/OSF.IO/RFK5T

Search strategy
A systematic search was conducted using the following elec-

Eligibility criteria
Intervention studies that provided information regarding the effects of physical exercise in HT or SCH were considered eligible.Investigations were excluded if: a) the research lacked a control or comparison group; b) physical exercise was performed in combination with other nonpharmacological therapies; c) the intervention was based on the performance of a single exercise training session; d) the full-text of the study was not available; and e) the research was not written in English, Portuguese or Spanish language.

Study selection
Two authors screened the titles and abstracts of the identified studies for eligibility.After independently reviewing the selected studies for inclusion, these were compared by both authors to reach an agreement.Once the agreement had been reached, a full-text copy of every potentially relevant study was obtained.If it was unclear whether the study met the selection criteria, advice was sought from a third author and a consensus was reached.The reference lists of the articles selected, as well as studies that quoted them were checked for potential new articles eligible for this review.

Data extraction
Study type, information on participants' characteristics, interventions, measured outcomes and results were extracted from the original reports by one researcher and checked by a second investigator.

Quality appraisal
The methodological quality of each randomized controlled trial (RCT) was retrieved from the Physiotherapy Evidence Database (PEDro).If a trial was not included in PEDro, two authors appraised its quality and disagreements were solved by consensus.The suggested cut-off points to categorize studies by quality were excellent (9-10), good (6)(7)(8), fair (4-5), and poor (<3) [11].The Methodological Index for Non-Randomized Studies (MINORS) [12] was used to determine the methodological quality of comparative studies.The MINORS instrument includes 12 items corresponding to an equal number of quality criteria for comparative studies.The items are scored 0 (not reported), 1 (reported but inadequate), and 2 (reported and adequate).The global ideal score is 24 points for comparative studies.The methodological quality of comparative studies was assessed by one author and then checked by a second author.In case of disagreement, advice from a third author was sought.High quality was considered if the total MINORS score was 17 or more, whereas a total score less than 17 was deemed as low quality [13].

Statistical analysis
We performed the meta-analysis calculations in Microsoft Excel with Meta-Essentials Workbooks [14].We used random effects model for all analysis and I2 was applied to assess statistical heterogeneity and inconsistency.The forest plot was made with the RevMan v5.4.1 software.

Results
We obtained 2832 records from the database search.After excluding duplicates, we screened the titles and abstracts of 1858 records, and subsequently, 74 articles were retrieved for the full-text assessment.Finally, 10 studies met the inclusion criteria and were included in the systematic review (Figure 1).
In total, 399 participants were included across the studies.The study's samples ranged from 20 to 100 participants.Only two studies included mixed samples [18,24], although according to the obtained data, almost all participants were female (97%).The characteristics of the participants differed between the samples, with age ranging from 8 up to 60 years.Only four studies [15,19,20,23] reported the mean ± SD age of the sample which was around 29.44 ± 6.34 years old.One study included young populations (age range: 8-15 years) [19].
Four studies indicated that the samples were composed of individuals with SCH [16,18,19,21].In the remaining six studies, the type of HT was not reported.

Quality appraisal
The methodological quality of the seven reviewed RCTs ranged from 'poor' [15,18] to 'fair" [16,17,[19][20][21].Out of the three comparative studies, one of them was judged to be of low methodological quality [24] and two studies were considered of high quality [22,23].A full description of the quality analysis is also provided (Electronic Supplementary Material, Tables S1 and S2).
Aerobic exercise was found to be not more effective than usual treatment in controlling triiodothyronine levels [18] and did not have a significant impact on anti-thyroid peroxidase antibodies levels [16,21] or symptoms of HT [21].

Anthropometrical measures
Three studies included body mass as an outcome [18,19,21], with two of them showing significant results [18,19].Body mass index (BMI) was measured in four studies [16,19,21,24].Two of them reported significant effects of exercise in this variable [19,24].Body fat was found to be significantly reduced after exercising, while waist circumference remained unchanged [19].

Metabolic health
Exercise had a significant effect on lipid profile by reducing triglyceride levels and increasing high-density lipoprotein values [22].Additionally, it was found to improve insulin resistance [19] and fasting blood sugar levels [23].

Fitness measures
Exercise led to significant changes in cardiorespiratory fitness through improvements in forced expiratory volume in one second and forced vital capacity, and maximal oxygen consumption [17].Mean response time to exercise, systolic blood pressure and rating of perceived exertion were also positively affected by the training programs, while heart rate kinetic and diastolic blood pressure remained unchanged [16] Combining aerobic and resistance exercise led to significant improvements on physical performance [24].

Discussion
In this research, the scientific evidence regarding the effectiveness of physical exercise as a coadjutant therapy for people with HT was examined and critically reviewed.To achieve this objective with maximum accuracy, the search was not limited to RCTs, but also included comparative studies.This approach is useful when reviewing the feasibility, intervention characteristics, and adverse effects of non-pharmacological therapies [25].Identifying these details through a broader range of results can assist clinicians and therapists in deciding whether to recommend exercise to individuals with HT as part of their treatment process.
The systematic search indicated that few studies, of diverse methodological quality have addressed the efficacy of exercise in HT, which somehow limits the synthesis and interpretation of the obtained results.Indeed, because of this heterogeneity in the data, while certain trends regarding the effects of exercise can be observed, it remains challenging to arrive at definitive and unequivocal conclusions.In spite of this, from the analysis of the reviewed investigations, we can extract findings of some importance.
For instance, it has been observed that adherence to exercise in people with HT is challenged by exercise intolerance, due to the active role that the thyroid hormones have on regulating cardiovascular, respiratory, and muscle functions.Indeed, exercise intolerance has been reported both among untreated patients and in those with OVH, or SCH (although to a lesser extent) [26].According to the reviewed studies, exercise appeared to be safe and well-tolerated.Adverse effects or dropouts due to participation in exercise training programs were scarcely reported.Moreover, the studies conducted by Almas et al. [16] and Bhatnagar et al. [17] indicated that participation in training programs can improve response to exercise and physical fitness, which are strongly related to exercise tolerance.Low physical fitness has also acknowledged as an exercise barrier in this population [4].These findings provide preliminary scientific evidence suggesting that supervised exercise can be safely prescribed in adequately treated patients with HT.
Another noteworthy finding is that exercise training did not have a significant effect on thyroid function.The pooled data indicated that levels of thyroid hormones FT4 and T4 were not significantly altered after exercise programs.Furthermore, no significant differences were found when comparing exercise and control groups in this regard.Based on the characteristics of the samples included in the analysed studies, it can be hypothesized that most of the patients had SCH, as the diagnosis of HT was mainly based on TSH levels above normal and T4 levels within the normal range and were receiving pharmacological replacement therapy.In this population, scientific evidence supporting the efficacy of pharmacological treatment is weak [5], as it seems to be the case of exercise, judging from the findings of this review.
It has been hypothesised that exercise can enhance thyroid function through various mechanisms, such as reducing body weight, promoting the secretion of thyroid hormones, improving blood flow to the thyroid gland, and increasing tissue sensitivity to thyroid hormones [27].However, alterations in TH levels appear to be more prominent at high exercise intensities, are contingent on individuals' fitness levels, and have primarily been observed in athletes [28,29].Consequently, it may be challenging to attain substantial changes in thyroid function through exercise programs performed at moderate or submaximal intensities by individuals with hypertension.
Notably, SCH may be associated with an increased risk of heart failure, coronary artery disease events, and mortality from coronary heart disease.Due to the lack of evidence regarding whether pharmacological treatment can prevent these risks, the rationale for treatment is based on the potential for decreasing the risk of adverse cardiovascular events [30].In this regard, it is worth noting that in the study by Bhatnagar et al. [17], exercise improved cardiorespiratory fitness.Scientific evidence has shown that cardiorespiratory fitness is associated with improved survival and decreased incidence of cardiovascular diseases and other comorbidities, including heart failure [31].Therefore, exercise can be considered a useful coadjuvant preventive therapy.This assumption is supported by data from three studies found in this review, which confirmed that exercise improved lipid profile, a known risk factor for cardiovascular disease frequently present among people with SCH [32] Obesity is another risk factor for cardiovascular disease that should be accounted for.Obesity and HT are strongly related.This relationship is likely to be bidirectional, with HT affecting weight, but obesity also influencing thyroid function [33].HT has also been linked to changes in body weight, and it has shown to correlate with higher BMI, representing a risk factor for overweight and obesity [34].According to the findings of the present review, exercise might have a significant positive effect on BMI.In these studies, submaximal aerobic exercise and resistance training programs were implemented.Both of these exercise regimens have been demonstrated to elevate energy expenditure and diminish excess adipose tissue [35,36].This may be an important reason to encourage people with HT to exercise, as it can help achieve optimal management of this disease.
Patients with OVH and SCH show greater dissatisfaction with self-perceived health status in comparison with healthy population, primary due to the presence of clinical symptoms such as fatigue, anxiety or depression [37].None of the reviewed studies included these symptoms as outcomes.However, studies included in this review have reported improvements in self-perceived health and self-esteem among patients with HT who participated in exercise programs.Both of these aspects have been considered important for improving quality of life, which is often reduced in people with HT [38].This finding aligns with previous research, which has suggested that participation in exercise programs aimed at improving fitness and overall health can lead to enhanced self-perceptions.These improved self-perceptions, in turn, contribute to more positive self-views, ultimately leading to an enhanced sense of well-being [39].These findings provide a basis for future studies aimed at exploring the impact of exercise on patients' quality of life, an area of research that has been under-explored [40].
A final aspect worth of interest in this review is the type of exercise that could be more appropriate to prescribe to people with HT.Aerobic exercise was the most frequently proposed type, with only two studies comparing this modality versus resistance training.The obtained findings indicate that the latter might be more effective for controlling TSH levels and lipid profile.The combination of both exercise modalities also seemed to be more efficient than performing solely aerobic exercise.This information can help guide clinicians and health practitioners in developing exercise programs that are tailored to the individual needs of their patients with HT.However, the existing data does not provide sufficient information to formulate specific exercise prescription guidelines, accounting for factors like the patient's ongoing treatment or their levels of TSH, FT4, and free triiodothyronine (FT3).Consequently, we can only establish general recommendations on this matter until further high-quality research is conducted.
A subset of patients with HT are not satisfied with their current therapy [41].Therefore, alternative rehabilitation strategies are necessary.This review was conducted to provide valuable information on the potential benefits of prescribing exercise to people with IT.However, certain methodological issues hindered the fulfilment of this objective.First, there was a lack of clear description regarding the type of HT exhibited by the participants in some of the reviewed studies.From our interpretation, the results showed here might only be representative of women with SCH.Second, although a meta-analysis on the effects of exercise on thyroid function could be performed, few studies with a considerable heterogeneity were included.Thus, further RCTs are needed to confirm the lack of significant effects encountered in this review.Thirdly, most of the interventions analysed focused on the effects of aerobic exercise, resulting in limited information on the impact of other exercise modalities on people with HT.Finally, there are limitations related to the fact that we did not review the grey literature, and to the publication bias, which may have conditioned the results showed here.
In conclusion, exercise does not have a significant impact on thyroid function, although its practice can lead to improvements in physical fitness, body composition, and metabolic health.Nevertheless, the existing body of knowledge comes from a limited number of studies, mostly focused on women with SCH, providing low-to-moderate certainty of evidence, indicating the need for further investigations in this regard.

Figure 1 .
Figure 1.PriSMa (Preferred reporting items for systematic reviews and meta-analyses) study flow diagram.

Figure 2 .
Figure 2. forest plot for the effect of exercise vs control on tSH levels.negative numbers indicate lower tSH after the intervention.