Different Relationships Between Thyrotropin and Muscle Strength According to Sex and Age in Euthyroid Koreans (The 6th Korea National Health and Nutritional Examination Survey 2014

Abstract

Background:

Changes in muscle mass and strength can be caused by multiple endocrine factors, including thyroid dysfunction. However, the relationship between thyroid function and muscle strength in euthyroid individuals is not clear. In the present study, we investigated the relationship between thyroid function and handgrip strength (HGS) in euthyroid Koreans, especially according to sex and age.

Methods:

This was a population-based, cross-sectional study from the 6th Korea National Health and Nutrition Examination Survey including 2894 Koreans (1487 men and 1407 women) aged ≥19 years. Serum thyrotropin (TSH) and free thyroxine (fT4) levels were measured. HGS was measured using a digital grip strength dynamometer.

Results:

Serum TSH level, but not serum fT4 level, was significantly associated with HGS in men, but neither TSH nor fT4 level was associated with HGS in women. Serum TSH showed a negative association with HGS in men aged <65 years (n = 1376; β = −0.566, p = 0.008), but a positive association in men aged ≥65 years (n = 111; β = 1.158, p = 0.010) after adjusting for confounders. HGS decreased as TSH tertile increased in men aged <65 years (p for trend = 0.010), but increased with TSH tertile in men aged ≥65 years (p for trend = 0.009) after adjusting for confounders. Odds ratios (ORs) for the lowest quartile of HGS increased in the highest tertile of TSH among men aged <65 years (OR = 1.657 [95% confidence interval {CI} 1.099–2.500], p = 0.006) and decreased in the highest tertile of TSH among men aged ≥65 years (OR = 0.176 [CI 0.032–0.966], p = 0.034) after adjusting for confounders.

Conclusions:

In euthyroid Koreans, serum TSH levels were significantly associated with HGS only in men and this relationship was found to depend significantly on age. These findings suggest that age has a distinct influence on the effect of even subtle change of thyroid function on muscle strength in men.

Introduction

Thyroid hormones (THs) are essential for cellular energy homeostasis and regulation and virtually affect the function of every organ system. In skeletal muscle, THs participate in multiple biochemical events, including contractile function, energy metabolism, myogenesis, and regeneration. For this reason, patients with overt hypo- or hyperthyroidism show various muscle abnormalities ranging from asymptomatic creatine kinase elevation to rhabdomyolysis, although the pathophysiology of these changes depends on the type of thyroid dysfunction (1,2). Interestingly, recent studies have demonstrated that regulations of glucose and lipid metabolism in skeletal muscle by THs may link thyroid dysfunction to some metabolic diseases (3,4).

Sarcopenia is a progressive and generalized skeletal muscle disorder characterized by low muscle mass and poor muscle quality and strength, increasing risks of falls, fractures, physical disability, and death (5). Sarcopenia is largely attributable to aging, and THs are known to be associated with aging-associated pathologies (6). In this context, previous clinical studies have demonstrated an association between thyroid dysfunction and sarcopenia in the elderly (7 –9), and that elderly individuals exhibit decreased muscle mass and/or strength with increased frailty even in the presence of subclinical thyroid dysfunctions such as subclinical hypo- or hyperthyroidism.

However, little data are available on the relationships between thyroid function and sarcopenia in young or middle-aged adults, although sarcopenia may occur earlier in life by other factors beyond aging, including thyroid dysfunctions (5). Furthermore, associations between THs and changes in skeletal muscle mass or strength in euthyroid individuals according to sex and age have rarely been reported (10,11). In the present study, we investigated the relationship between serum TH levels and muscle strength, which is the most important determinant of sarcopenia, in euthyroid Korean individuals with ages ranging from 19 to 80 years according to sex, using the nationally representative data collected during the 6th Korea National Health and Nutritional Examination Survey (KNHANES VI).

Materials and Methods

Study participants

Participants in this study were recruited from the second (2014) and third (2015) years of the KNHANES VI because handgrip strength (HGS) measurements were only performed during this period. KNHANES VI is a cross-sectional, nationwide survey that uses a stratified, multistage, clustered probability sampling method to select a representative sample of noninstitutionalized, civilian Koreans (12). The survey consisted of a health interview, a health examination, and a nutrition survey. Data were collected by household interview and during standardized physical examinations conducted at mobile examination centers. All participants provided informed consent. The KNHANES database is publicly available in English on the KNHANES website.

Of the 14,930 individuals who participated in KNHANES 2014–2015, we initially selected those aged ≥19 years (n = 11,921, range 19–80 years old) and then excluded those with missing thyroid function tests (n = 7876) or HGS data (n = 1830). During KNHANES VI, about 2400 individuals aged ≥10 years were selected each year for the measurement of thyroid function using stratified subsampling and weighted to represent the total Korean population (13). HGS was measured in all participants aged ≥19 years after excluding those who were not suitable for the measurement due to reasons such as no hands, arms, or thumbs; paralysis of hands; cast on hands or fingers; bandage on hands or wrist surgery within the prior week (10). We next selected participants with serum thyrotropin (TSH) and free thyroxine (fT4) levels within the reference range (n = 3635) after excluding participants with subclinical hypothyroidism (n = 236), hyperthyroidism (n = 49), over hypothyroidism (n = 36), or hyperthyroidism (n = 22). Among those with a euthyroid status, we additionally excluded individuals previously diagnosed with any thyroid diseases, including hypothyroidism, hyperthyroidism, or thyroid cancer (n = 96).

Although sarcopenia is largely attributable to aging, there are many other causal chronic diseases (5) and these are related to nonthyroidal illness. Therefore, we excluded individuals who were diagnosed with chronic diseases, including chronic liver disease, chronic kidney disease, chronic obstructive pulmonary disease, pulmonary tuberculosis, or cancer (n = 648). We also excluded pregnant participants (n = 5) since the metabolism of THs changes during pregnancy. The remaining 2894 participants aged from 19 to 80 years (1487 men and 1407 women) constituted the study cohort.

Lifestyle, anthropometric, and dietary parameters

All participants underwent a thorough physical examination. Age, weight, height, smoking and drinking habits, physical activity, and exercise habits were recorded. Smoking was categorized as never, past, or current. Heavy alcohol drinking was defined as the consumption of ≥7 or ≥5 drinks at one time, more than twice a week for men and women, respectively. Nutrient intake was estimated using a multiple-pass 24-hour dietary recall technique, and protein intake was measured on a food item basis. Aerobic physical activity was defined as >150 minutes of moderate-intensity physical activity or >75 minutes of high-intensity physical activity per week. Resistance exercise was defined as exercises such as push-ups, sit-ups, dumbbell or barbell lifts, or chin-ups more than once per week. Weight (kg) and height (cm) were measured with participants wearing light clothing without shoes. Body mass indices (BMI, kg/m²) were calculated by dividing weight by height squared. Self-report questionnaires were used to assess menopausal status.

Biochemical measurements

Blood samples were immediately refrigerated, transported to a Central Testing Institute in Seoul, and analyzed within 24 hours. Serum TSH and fT4 levels were measured using electrochemiluminescence immunoassays (Roche Diagnostics, Mannheim, Germany) using an E-TSH kit (Roche Diagnostics), for which the reference range was considered to be 0.35–5.50 mIU/L, or an E-Free T4 kit (Roche Diagnostics), for which the reference range was 0.89–1.76 ng/mL, respectively. Serum creatinine levels were measured using a Hitachi automatic analyzer 7600 (reference range, 0.5–1.4 mg/dL).

Measurement of HGS

HGS was measured using a digital grip strength dynamometer (T.K.K 5401, Takei Scientific Instruments Co., Ltd., Tokyo), which measures between 5.0 and 100.0 kg of force with an accuracy of ±0.1 kg and has an adjustable span. During HGS measurements, participants were asked to stand upright with their feet at hip-width apart and to look forward with elbows fully extended. The dynamometer was held using the dominant hand in a neutral, comfortable position (not flexed or extended) with index finger in 90° of flexion. Participants were instructed to squeeze the grip continuously at full force for at least 3 seconds. Approximately 60 seconds was then allowed for recovery between measurements. Grip strength was defined as the average of the results of three trials (14).

Statistical analysis

The analysis was conducted using sex and age (<65 and ≥65 years) groups. Since many countries define older adults as those with a chronological age of 65 years or older, and previous studies also demonstrated that a rapid decline of HGS is observed around the age of 60 years (15), which was also the case in our study subjects (Supplementary Fig. S1), we chose the cutoff as 65 years. Continuous and categorical variables are expressed as means ± standard errors and percentages, respectively, if not otherwise specified.

Multiple linear regression analyses were conducted to determine the nature of associations between HGS and TSH or fT4 for men and women aged <65 or ≥65 years. The confounders adjusted for were as follows: age, BMI, creatinine, alcohol consumption, smoking, aerobic physical activity, resistance exercise, protein intake for men, and additionally menopause for women <65 years old on the basis of clinical applicability as well as the correlation analysis with TSH, fT4, or HGS. Baseline characteristics according to TSH tertiles were compared using one-way analysis of variance for continuous variables or the chi-square test for categorical variables for men according to age. To analyze HGS changes with respect to TSH tertiles for different ages in men, multivariate-adjusted least-square means with 95% confidence intervals (CIs) were estimated and compared by analysis of covariance adjusted for age, BMI, creatinine, alcohol consumption, smoking, aerobic physical activity, resistance exercise, and protein intake.

We also calculated odds ratios (ORs) for low HGS, which was defined as a HGS value in the lowest quartile for each age group (≤37.49 and ≤32.08 kg for men aged <65 and ≥65 years, respectively), according to TSH and TSH tertiles after adjusting for age, BMI, creatinine, alcohol consumption, smoking, aerobic physical activity, resistance exercise, and protein intake in men. The Complex Samples Plan, which is available as the complex samples option in SPSS version 18.0 (SPSS, Inc., Chicago, IL), was used for all analyses to account for sample weighting. Statistical significance was accepted for p values of <0.05.

Results

Baseline characteristics of the study subjects

The clinical characteristics of the 1487 men (1376 < 65 years old and 111 ≥ 65 years old) and the 1407 women (1326 < 65 years old and 81 ≥ 65 years old) are shown in Table 1. For both men and women, subjects aged <65 years had stronger HGS, consumed more protein, smoked more, and were more physically active than subjects aged ≥65 years (p < 0.001–0.031). For men, subjects aged <65 years had a slightly higher serum fT4 level and drank more than subjects aged ≥65 years (p = 0.001 and 0.026, respectively). For women, subjects aged <65 years performed more resistance exercise than subjects aged ≥65 years (p = 0.048).

Table 1.

Baseline Characteristics of the Study Subjects

Variables	Men			Women
Variables	<65 years (n = 1376 )	≥65 years (n = 111)	p	<65 years (n = 1326 )	≥65 years (n = 81)	p
Age (years old)	39.8 ± 0.4	67.8 ± 0.3	<0.001	35.4 ± 0.4	68.1 ± 0.4	<0.001
BMI (kg/m²)	24.4 ± 0.1	23.8 ± 0.4	0.116	22.4 ± 0.1	24.1 ± 0.5	0.001
Creatinine (mg/dL)	0.95 ± 0.00	0.94 ± 0.02	0.635	0.70 ± 0.00	0.72 ± 0.01	0.109
TSH (mIU/L)	2.27 ± 0.03	2.27 ± 0.11	0.997	2.42 ± 0.03	2.43 ± 0.16	0.969
fT4 (ng/mL)	1.30 ± 0.01	1.24 ± 0.02	0.001	1.22 ± 0.01	1.20 ± 0.02	0.431
HGS (kg)	42.07 ± 0.26	35.01 ± 0.63	<0.001	24.65 ± 0.15	21.16 ± 0.66	<0.001
Protein intake (g/day)	91.6 ± 1.8	75.7 ± 4.3	0.001	64.5 ± 0.9	57.8 ± 4.4	0.031
Current smoker	40.6%	24.1%	0.003	6.2%	1.2%	0.011
Alcohol consumption	18.6%	9.1%	0.026	5.9%	0.0%	0.052
Aerobic physical activity	60.1%	46.7%	0.026	57.4%	30.8%	<0.001
Resistance exercise	42.8%	41.8%	0.871	26.6%	15.8%	0.048

Results are expressed as means ± SEs or percentages unless otherwise specified. p-Values were determined using the Student's t-test or the chi-square test.

BMI, body mass index; fT4, free thyroxine; HGS, handgrip strength; SEs, standard errors; TSH, thyrotropin.

Associations between HGS and TSH or fT4 in men and women according to age

Multiple linear regression analyses were conducted to examine associations between HGS and serum TSH or fT4 levels by sex and age (Table 2). For men <65 years old, serum TSH was negatively associated with HGS after adjusting for age, BMI, creatinine, alcohol consumption, smoking, aerobic physical activity, resistance exercise, and protein intake (β = −0.566, p = 0.008). However, serum TSH was positively associated with HGS after adjusting for confounders in men ≥65 years old (β = 1.158, p = 0.010). These results indicated that one mIU increase of TSH was related to a 0.5 kg decrease and 1.1 kg increase of HGS in men aged <65 and ≥65 years, respectively. No significant association was observed between serum fT4 and HGS in men after adjusting for confounders regardless of age. For women, no significant association was observed between HGS and TSH or fT4 regardless of age after adjusting for confounders (Table 2).

Table 2.

Multivariate Analyses to Determine the Independent Association Between Thyrotropin and Handgrip Strength

	Men						Women
	<65 years			≥65 years			<65 years			≥65 years
	β	SE	p	β	SE	p	β	SE	p	β	SE	p
TSH with HGS	−0.566	0.212	0.008	1.158	0.435	0.010	−0.001	0.137	0.993	0.021	0.654	0.975
fT4 with HGS	1.118	1.456	0.443	0.728	3.561	0.839	0.134	1.093	0.902	−1.096	4.520	0.810

p-Values were generated by multiple linear regression analysis after adjusting for age, BMI, creatinine, alcohol consumption, smoking, aerobic physical activity, resistance exercise, and protein intake, and for menopause in women <65 years old.

HGS according to TSH tertile in men by age

To clarify whether the association between TSH and HGS is gradual, we divided male subjects into TSH tertiles (Table 3). Since an independent association between TSH and HGS was only found in men after adjustment, we performed further analyses on men aged <65 or ≥65 years. For men aged <65 years, serum fT4 and HGS gradually decreased with increasing TSH tertile (p for trends = 0.011 and 0.010, respectively), serum creatinine gradually increased (p for trend <0.001), and the percentage of current smokers decreased (p < 0.001). For men aged ≥65 years, serum fT4 was not significantly influenced by TSH tertile and HGS gradually increased on increasing TSH tertile (p for trend = 0.011) (Table 3).

Table 3.

Baseline Characteristics According to Thyrotropin Tertile in Men by Age

Variables	T1	T2	T3	p for trend
<65 years old	n = 462	n = 457	n = 457
TSH range (mIU/L)	0.41–1.63	1.64–2.53	2.54–5.50
Age (years old)	39.8 ± 0.6	39.8 ± 0.6	40.0 ± 0.7	0.841
BMI (kg/m²)	24.3 ± 0.2	24.4 ± 0.2	24.3 ± 0.2	0.993
Creatinine (mg/dL)	0.925 ± 0.006^*	0.953 ± 0.007^*	0.970 ± 0.006	<0.001
fT4 (ng/mL)	1.31 ± 0.01^*	1.32 ± 0.01^*	1.28 ± 0.01	0.011
HGS (kg)	42.45 ± 0.41^*	42.81 ± 0.44^*	40.98 ± 0.43	0.010
Protein intake (g/day)	89.8 ± 2.9	94.0 ± 3.8	90.9 ± 2.9	0.806
Smoking	51.6%	42.4%	33.4%	<0.001^†
Alcohol consumption	21.3%	19.5%	15.4%	0.087^†
Physical activity	60.8%	59.3%	60.2%	0.929^†
Resistance exercise	39.9%	42.4%	45.8%	0.242^†
≥65 years old	n = 37	n = 38	n = 36
TSH range (mIU/L)	0.42–1.75	1.76–2.75	2.76–4.93
Age (years old)	68.5 ± 0.7	67.5 ± 0.5	67.3 ± 0.3	0.135
BMI (kg/m²)	24.1 ± 0.4	22.9 ± 0.6	24.4 ± 0.8	0.744
Creatinine (mg/dL)	0.933 ± 0.040	0.946 ± 0.031	0.942 ± 0.026	0.845
fT4 (ng/mL)	1.25 ± 0.04	1.23 ± 0.03	1.23 ± 0.04	0.616
HGS (kg)	32.97 ± 1.18^*	35.71 ± 0.88	36.67 ± 0.93	0.011
Protein intake (g/day)	82.4 ± 8.0	70.5 ± 4.3	73.6 ± 9.1	0.455
Smoking	34.3%	28.9%	17.6%	0.284^†
Alcohol consumption	16.2%	10.5%	2.8%	0.156^†
Physical activity	55.9%	37.8%	47.1%	0.313^†
Resistance exercise	45.9%	28.9%	38.9%	0.312^†

Results are expressed as means ± SEs or as percentages unless otherwise specified. p-Values for trends were generated by simple linear regression analysis.

^*p < 0.05 versus the third tertile as determined by post hoc analysis.

†

p-Values were generated using the chi-square test.

T1, the first tertile; T2, the second tertile; T3, the thrid tertile.

To better understand the independent effects of TSH on HGS, we adjusted for all confounders, that is, age, BMI, creatinine, alcohol consumption, smoking, aerobic physical activity, resistance exercise, and protein intake (Table 4). For men aged <65 years, HGS showed a decreasing trend on increasing TSH tertile after adjusting for confounders (p for trend = 0.010). Post hoc analysis showed subjects in the highest TSH tertile had significantly lower HGS than subjects in lower tertiles. However, for men aged ≥65 years, HGS showed an increasing trend on increasing TSH tertile after adjusting for confounders (p for trend = 0.009). Furthermore, post hoc analysis showed that subjects in the highest TSH tertile had significantly higher HGS than subjects in the lowest TSH tertile (Table 4).

Table 4.

Handgrip Strength According to Thyrotropin Tertiles in Men by Age

Variables	T1	T2	T3	p for trend
<65 years old	n = 462	n = 457	n = 457
TSH range	0.41–1.63	1.64–2.53	2.54–5.50
HGS	42.64 ± 0.43^*	42.53 ± 0.43^*	41.08 ± 0.47	0.010
≥65 years old	n = 37	n = 38	n = 36
TSH range	0.42–1.75	1.76–2.75	2.76–4.93
HGS	33.61 ± 0.84^*	35.65 ± 0.84	36.76 ± 1.05	0.009

Results are expressed as means ± SEs. p-Values were generated by multiple linear regression analysis adjusted for age, BMI, creatinine, alcohol consumption, smoking, aerobic physical activity, resistance exercise, and protein intake.

^*p < 0.05 versus the third tertile as determined by post hoc analysis.

Risk of low HGS according to TSH and TSH tertile in men by age

We next investigated the risk of low HGS, which we defined as an HGS value in the lowest quartile in the two age groups (≤37.49 and ≤32.08 kg for men aged <65 and ≥65 years, respectively), according to TSH and TSH tertiles (Table 5). After adjusting for all confounders, including age, BMI, creatinine, alcohol consumption, smoking, aerobic physical activity, resistance exercise, and protein intake, the OR for low HGS in men <65 years old increased with TSH (OR = 1.176 [CI 1.001–1.382], p = 0.048). Multiple logistic regression analyses revealed that the OR for low HGS was significantly higher in the highest TSH tertile than in the lowest TSH tertile (OR = 1.657 [CI 1.099–2.500], p = 0.006) in men <65 years old. For men ≥65 years old, the OR for low HGS was significantly lower in the highest and second highest TSH tertiles than in the lowest TSH tertile (OR = 0.176 [CI 0.040–0.776] and OR = 0.176 [CI 0.032–0.966], p = 0.034, respectively).

Table 5.

Odds Ratios and 95% Confidence Intervals of Low Handgrip Strength with Respect to Serum Thyrotropin Level or Tertile in Men

	<65 years old			≥65 years old
	OR	CI	p	OR	CI	p
TSH	1.176	1.001–1.382	0.048	0.462	0.206–1.034	0.060
TSH tertiles
T1	Ref.		0.006	Ref.		0.034
T2	0.870	0.556–1.362		0.176	0.040–0.776
T3	1.657	1.099–2.500		0.176	0.032–0.966

p-Values were generated by multiple logistic regression analysis adjusted for age, BMI, creatinine, alcohol consumption, smoking, aerobic physical activity, resistance exercise, and protein intake. Low HGS was defined as an HGS value in the lowest quartile for both age groups. (Ranges of HGS values in each quartile according to age: 19.60–37.49 kg for Q1, 37.50–42.02 kg for Q2, 42.03–46.89 kg for Q3, and 46.90–66.70 kg for Q4 in men <65 years old and 19.30–32.08 for Q1, 32.09–35.42 for Q2, 35.43–38.85 for Q3, and 38.86–51.20 for Q4 in men ≥65 years old.)

Discussion

In this present study, we found that serum TSH, but not serum fT4, was significantly associated with HGS in euthyroid Korean men. On the contrary, no significant association was observed between serum TSH or fT4 and HGS in euthyroid Korean women. In euthyroid Korean men <65 years old, serum TSH was negatively associated with HGS and the risk of low HGS increased with TSH, whereas in euthyroid Korean men ≥65 years old, serum TSH was positively associated with HGS and the risk of low HGS decreased as TSH increased. These findings show that the relationship between TSH and HGS in euthyroid Koreans is highly dependent on sex and age.

Progressive age-related deterioration of skeletal muscle is a natural phenomenon, but it can have several severe consequences (16). Therefore, it is important to find and appropriately manage the elderly with sarcopenia. However, sarcopenia can also develop earlier in life as it has many other contributory causes beyond aging (15,17) such as malnutrition, endocrine dysfunction, neurodegenerative disease, and several chronic diseases.

Among these, thyroid dysfunctions are well-established causes of muscle pathologies. TH signaling principally targets skeletal muscle (18,19). At the cellular level, THs are key regulators of skeletal muscle development, regeneration, and metabolism. The effects of THs on skeletal muscle depend on the presence of TH transporters in the plasma membrane, the expressions of TH receptors, and hormone availability by type 2 or type 3 iodothyronine deiodinase activity in addition to serum TH levels (20). Therefore, even subtle changes in THs may affect muscle mass or quality. Moreover, some recent experimental studies have demonstrated the presence of TSH receptor in skeletal muscle, and thus suggested that TSH also directly affects skeletal muscle metabolism (21,22).

In the present study, we divided the participants into two age groups, with a cutoff of 65 years old. Sixty-five years old is a widely used cutoff value for older adults in many countries and in our study, the effects of TSH on HGS across the age also seemed to be changed after 65 years old (from inverse to positive association), although this effect modification was not perfectly linear (Supplementary Fig. S2). In this study, the mean HGS of men aged <65 and ≥65 years was 42.07 and 35.01 kg and that of women aged <65 and ≥65 years was 24.65 and 21.16 kg, respectively.

These were similar to a recent study demonstrating age- and sex-stratified reference HGS values in the Korean population, in which mean HGS for men aged ≥65 years was 33.63 kg (range: 8.1–53.2 kg) and those for women aged ≥65 years was 20.53 kg (range: 6.1–35.4 kg) (23). An another recently published study showed that the peak in HGS of the Korean population was in 35–39 years of age, and therefore, the cutoff values for weak HGS (−2 standard deviation values of healthy young adults) were <28.9 and <16.8 kg in men and women, respectively (14). Therefore, the mean HGS values of older adults (≥65 years old) in this study were better than what could be expected in Korean sarcopenic subjects, which might anticipate a generally good physical ability of them.

In the present study, we found that sex influenced the association between serum TSH and HGS. More specifically, it significantly influenced this association in men, but not in women. Under normal conditions, androgens and estrogens contribute to sex-associated differences in skeletal muscle morphology and function (24). Briefly, testosterone is a potent anabolic factor that promotes protein synthesis and muscle regeneration (25,26), and estrogen has been shown to influence the balance between catabolic and anabolic processes in skeletal muscle (27,28), although it is a relatively new field of study in muscle physiology. Moreover, age-associated decreases in muscle mass, muscle strength, and physical function, and increases in fat mass, are known to be more prominent in men than in women (29,30), which by extension suggests the possibility that muscle strength is more affected by thyroid function in men.

The lack of an association between serum TSH and HGS in women in the present study may also have been caused by stratification by age, rather than menopausal status, as the effects of estrogen on skeletal muscle dramatically change after menopause (24). However, we adjusted all analyses of women <65 years old with respect to menopausal status to minimize the confounding effect of sex hormones. Moreover, when we additionally analyzed the relationship between TSH and HGS in women according to menopausal status, no significant association was observed in both pre- and postmenopausal women (data not shown).

In previous clinical studies, the relationship between thyroid function and sarcopenia has usually been investigated in elderly patients with overt or subclinical thyroid dysfunction (7 –9), and few studies have addressed this relationship in euthyroid subjects of wide range of age. In this context, the present study is one of the first to investigate the relationship between thyroid function and muscle strength in euthyroid young, middle-aged, and older adults. We found that age had a distinct influence on the association of subtle change of thyroid function within the reference range with muscle strength. This finding is in line with a previous study performed in a German population (31), which showed that TSH was significantly inversely associated with grip strength in younger participants up to an age of ∼60 years, but not in older adults. Similar to that study, the relationship of serum TSH with HGS was completely different between euthyroid men aged <65 and ≥65 years in our study. In men aged <65 years, serum TSH exhibited a negative relationship with HGS, and serum fT4 was negatively related with TSH tertile, the latter of which is in line with the feedback system of the hypothalamus/pituitary/thyroid axis (32). These findings suggest that the lower HGS of participants with a higher serum TSH was caused by attenuation of the positive effect of fT4 on skeletal muscle, as THs are necessary for normal postnatal skeletal muscle development and maturation in earlier life (20).

On the contrary, in euthyroid men aged ≥65 years, serum TSH was positively associated with HGS. It is known that there is a negative association between TH levels and aging due to the effects of TH on mitochondria, heat production, membrane composition, inflammatory responses, and stem cell renewal (33,34). The aging process is also characterized by the anabolic/catabolic imbalance resulting in an elevated catabolic rate (35). In this condition, THs may enhance catabolic changes and accelerate muscle mass and strength losses. Therefore, lower serum TSH might have more negative effects on the aging process, with a higher catabolic rate and subsequent loss of muscle strength in older adults as lower levels of TSH indicate a relatively higher level of fT4. In line with this hypothesis, a previous study performed in older adults showed that increasing fT4 was related to lower isometric grip strength. This study suggested that a lower activity of the TH axis is beneficial during the aging process as an adaptive mechanism to prevent excessive catabolism (36). Finally, there are also possibilities that serum TSH has direct negative effects on skeletal muscle strength in young and middle-aged individuals, but positive effects in older adults. However, if correct, the responsible mechanisms require further investigation.

In the present study, β coefficients for TSH on HGS in the multivariate analyses (Table 2) showed that in men aged <65 years, a 1 mIU increase of TSH was related to a 0.5 kg decrease of HGS, while in those aged ≥65 years, a 1 mIU increase of TSH was related to a 1.1 kg increase of HGS. In a recent study that evaluated the association of serum testosterone level with HGS, an important determinant of HGS in men, in male participants aged ≥40 years, the β coefficient for free testosterone on HGS was only 0.109 (37). In this context, we could assume that even a subtle change of thyroid function might be strong enough to influence muscle strength in men regardless of age.

Based on recent research, muscle strength has been regarded the most important parameter for sarcopenia (5). Moreover, there were also studies suggesting that muscle strength is a predictor of future activity of daily living in the older adult population (38 –41). In another previous study, including young, middle-aged, or older adults, low HGS was associated with poor quality of life (QoL) (42). Although our study was cross sectionally designed, we could assume that in the older male adults, lower TSH levels within the reference range with weaker HGS may be related to a higher incidence of sarcopenia or functional deterioration in the near future. In this context, overcorrection of subclinical hypothyroidism may not be beneficial in this age group. Moreover, we could assume that higher TSH levels within the reference range with weaker HGS in young and middle-aged male adults may be related to sarcopenia and decrease in QoL. In this context, an effort to keep thyroid function in the middle of the reference range may be necessary in this age group.

This study has several strengths. First, we collected data from a nationwide Korean survey that includes more than 2000 male and female subjects across a wide age range. Second, this study is the first to investigate the relationship between thyroid function and muscle strength in euthyroid subjects with respect to sex and age. Third, KNHANES VI evaluated muscle strength using the HGS test. Recently, the European Working Group on Sarcopenia in Older People (EWGSOP2) focused on low muscle strength measured by the HGS test rather than low muscle mass as the most important determinant of sarcopenia according to scientific and clinical evidence accumulated over the past decade (5).

However, the study also has its limitations. First, the cross-sectional nature of the study means that we were unable to access the causal relationship between serum TSH and HGS. Second, serum fT4 was not found to be significantly associated with HGS, while direct actions of THs rather than TSH on muscle metabolism have been demonstrated (18 –20). However, most previous studies showing a significant association of fT4 with HGS or frailty (31,36,43 –45) included individuals with thyroid dysfunction, while we only analyzed euthyroid individuals. Serum TSH responds with logarithmical variations to minor changes in serum fT4 and free triiodothyronine values, and therefore, basal TSH is better as a first line test of thyroid function than fT4 (46,47). Therefore, the significant relationship of TSH, rather than fT4, with HGS in our study suggests that even subtle changes of thyroid function in euthyroid subjects have a significant effect on HGS. An ancillary analysis including participants with subclinical thyroid dysfunctions as well as euthyroidism showed no significant association of both TSH and fT4 with HGS in our study (Supplementary Table S1). Third, we did not apply the previously recommended cutoff values for low HGS by the EWGSOP2 (27 kg for men and 16 kg for women) (5) or the Asian Working Group for Sarcopenia (26 kg for men and 18 kg for women) (48). These recommended cutoff values were for older adults, while our study also included young adults as well as middle-aged and older adults. Therefore, we established our own definition for low HGS as values in the lowest quartiles in each age group in men (≤37.49 and ≤32.08 kg for men aged <65 and ≥65 years, respectively).

Fourth, we could not investigate the associations between thyroid function and muscle mass or physical performance (because no data were available in KNHANES VI), and these variables are used to confirm and evaluate the severity of sarcopenia. Fifth, the number of subjects aged ≥65 years was too small relative to subjects <65 years in this study. Nevertheless, the significance of association between TSH and HGS in men aged ≥65 years was quite strong. Finally, a similar clinical study investigated the association between TSH and HGS using KNHANES VI data (10). In this study, serum TSH levels at the lower end of the reference range were associated with low HGS in men aged ≥50 years. However, this recent study only included men aged ≥50 years and postmenopausal women with a euthyroid status, and it did not investigate young or all middle-aged adults.

In conclusion, this study shows that serum TSH levels are significantly associated with HGS only in euthyroid Korean men, and that these associations are quite different in men <65 or ≥65 years old. These findings suggest that age has a distinct influence on the effect of even subtle changes in thyroid function on muscle strength in men.

Footnotes

Author Disclosure Statement

The authors have no conflict of interest to declare.

Funding Information

This study was supported by grants from the National Research Foundation funded by the Korea government (Project No. 2017R1C1B2009158) and by Inha University Research Grant (INHA-57830).

Supplementary Material

Supplementary Figure S1

Supplementary Figure S2

Supplementary Table S1

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Different Relationships Between Thyrotropin and Muscle Strength According to Sex and Age in Euthyroid Koreans (The 6th Korea National Health and Nutritional Examination Survey 2014–2015)

Abstract

Background:

Methods:

Results:

Conclusions:

Introduction

Materials and Methods

Study participants

Lifestyle, anthropometric, and dietary parameters

Biochemical measurements

Measurement of HGS

Statistical analysis

Results

Baseline characteristics of the study subjects

Associations between HGS and TSH or fT4 in men and women according to age

HGS according to TSH tertile in men by age

Risk of low HGS according to TSH and TSH tertile in men by age

Discussion

Footnotes

Author Disclosure Statement

Funding Information

Supplementary Material

References