Serum Thyrotropin Levels and Blood Pressure Response to Exercise in a Population-Based Study

Abstract

Background:

Studies on the relation between thyroid function and exercise blood pressure (EBP) are rare and not population-based, and have yielded inconsistent results. The aim of this study was to investigate whether serum thyrotropin (TSH) levels are related to increased EBP.

Methods:

Cross-sectional data from 1438 subjects (711 women) aged 25–83 years without histories of cardiovascular diseases from the 5-year follow-up of the population-based Study of Health in Pomerania (SHIP-1) were analyzed. Blood pressure was measured at the 100 W stage of a symptom-limited bicycle ergometry test. Increased EBP was defined as a value above the sex- and age-specific 80th percentile of participants with serum TSH levels within the reference range (0.25–2.12 mIU/L).

Results:

There was no association between serum TSH levels and EBP after adjusting for sex, age, waist circumference, diabetes mellitus, smoking status, and antihypertensive medication. The odds for increased systolic EBP (odds ratio 1.24, 95% confidence interval 0.88; 1.76) and diastolic EBP (odds ratios 0.98, 95% confidence interval 0.70; 1.39) as well as for exercise-induced increase of systolic and diastolic blood pressure were not significantly different between subjects with high and low serum TSH levels within the reference range. Similar findings were found for both subjects with TSH levels below and above the reference range, respectively.

Conclusions:

We conclude that serum TSH levels are not associated with exercise-related blood pressure response.

Introduction

H igh resting blood pressure, even within the normal range, is associated with an increased risk of cardiovascular diseases (CVD), including atherosclerosis (1), stroke, and myocardial infarction (2,3). Further, exaggerated blood pressure responses to exercise are a risk factor for cardiovascular morbidity (4 –7) and mortality (8,9) and may provide more information for the evaluation of the risk of hypertension and cardiovascular events than resting blood pressure (10,11).

The factors predicting blood pressure responses to exercise are currently not well understood but may include high total cholesterol levels, high fasting triglyceride levels, high body mass index, and glucose intolerance (12), as well as endothelial dysfunction, increased left ventricular mass, and increased peripheral resistance (11). Although both overt hyper- and hypothyroidism are often associated with increased resting blood pressure (13,14), there is little information about the relation between thyroid dysfunction and exercise blood pressure (EBP). Available clinical studies (15 –17) are small, have limited statistical power, and yielded conflicting results. Thus, one study (17) reported increased blood pressure responses to exercise in 10 patients with long-term thyrotropin (TSH)-suppressive therapy, whereas two other studies (15,16) found no association between thyroid function and EBP in 12 (16) and 42 patients (15), respectively, with hyperthyroidism. Information regarding the potential relation between thyroid function and blood pressure responses to exercise from population-based studies is currently not available.

We performed a population-based study including more than 1400 subjects covering a wide range of serum TSH levels to investigate the relation between thyroid function and EBP. On the basis of available evidence that subclinical hypothyroidism has a stronger impact on the risk of CVD than subclinical hyperthyroidism (18 –20), we hypothesized that high serum TSH levels within and above the upper reference range are related to increased exercise systolic and diastolic blood pressures (ESBP/EDBP). The present investigation is a substudy of the Study of Health in Pomerania (SHIP).

Materials and Methods

Study population

The design of SHIP has been published previously (21,22). In brief, SHIP is a population-based study in the northeast area of Germany, which included 4308 subjects at baseline between 1997 and 2001. The first follow-up examination (SHIP-1) was conducted 5 years (mean 5.2 ± 0.5 years) after baseline, between 2002 and 2006, and comprised 3300 subjects (83.5% of the still eligible population) (23). All participants gave informed written consent. The study followed the recommendations of the Declaration of Helsinki and was approved by the ethics committee of the University of Greifswald.

A total of 1708 subjects (874 females) volunteered for a standardized progressive incremental exercise test on a cycle ergometer. We excluded 145 individuals who did not reach the 100 W stage of the exercise test, 32 persons with missing blood pressure data during the 100 W stage, and 4 participants with missing serum TSH data. Furthermore, participants with a previous history of CVD events (36 myocardial infarctions and 23 strokes) were not considered. In addition, we excluded 34 subjects with impaired left ventricular function defined by a fractional shortening <22% in women and <20% in men (24). Some subjects were excluded because of more than one CVD event. Thus, the final study population comprised 1438 subjects (711 women) aged 25–83 years who were available for the present analyses.

Computer-assisted interview

A computer-assisted personal interview was used to collect information on sociodemographic characteristics and medical conditions. Cigarette smokers were divided into never, ex-, and current smokers. Diabetes mellitus, history of myocardial infarction, and stroke were defined as self-reported physician's diagnosis. Subjects who participated in physical training for at least 1 hour a week for at least 4 months a year were classified as being physically active.

Present medication was recorded by a computer-aided method using the anatomic, therapeutic, and chemical (ATC) code. The following drugs were considered as antihypertensive medications: vasodilators used in cardiac diseases (ATC C01D), antihypertensives (ATC C02), diuretics (ATC C03), peripheral vasodilators (ATC C04), beta-blockers (ATC C07), calcium antagonists (ATC C08), angiotensin I-converting enzyme inhibitors, and angiotensin II receptor blockers (ATC C09).

Blood pressure and waist circumference

During SHIP core examinations after a 5-minute rest period, systolic and diastolic blood pressure were measured three times at the right arm of seated subjects using a digital blood pressure monitor (HEM-705CP; Omron Corporation, Tokyo, Japan) with each reading being followed by a further rest period of 3 minutes. The mean of the second and third measurements was calculated and used for evaluation of resting blood pressure. Hypertension was defined as a resting systolic blood pressure ≥140 mmHg, a resting diastolic blood pressure ≥90 mmHg, or use of antihypertensive medication. Waist circumference was measured to the nearest 0.1 cm using an inelastic tape midway between the lower rib margin and the iliac crest in the horizontal plane, with the subject standing comfortably with weight distributed evenly on both feet.

Serum TSH

Nonfasting blood samples were drawn from the cubital vein in the supine position. The samples were taken between 07:00 a.m. and 04:00 p.m. and analyzed immediately for all parameters. Serum TSH levels were analyzed by immunochemiluminescent procedures (Immulite 2000, Third generation; Diagnostic Products Corporation, Los Angeles, IL). According to the recently established TSH reference range (0.25–2.12 mIU/L) in the region (25), participants were divided into five groups as follows—group 1: <0.25 mIU/L; group 2: 0.25–0.65 mIU/L; group 3: 0.66–0.99 mIU/L; group 4: 1.00–2.12 mIU/L; group 5: >2.12 mIU/L. By definition, subjects in group 1 had decreased TSH levels, subjects in groups 2–4 had TSH levels within the reference range according to tertiles, and subjects in group 5 had increased TSH levels.

Exercise test

A symptom-limited exercise test using one calibrated electromagnetically braked cycle ergometer with an electrical seat height adjustment (Ergoselect 100; Ergoline, Bitz, Germany) was performed according to a protocol modified from Jones et al. (26) (stepwise increase in work load of 16 W after every minute, starting with 20 W). The procedure was continuously monitored by a physician. In the absence of chest pain and ECG abnormalities, all tests were continued as symptom-limited (volitional exertion, dyspnea, or fatigue), while patients were encouraged to reach maximal exhaustion. All tests were performed in room air according to current guidelines for exercise testing (27,28). Systolic and diastolic blood pressure were measured once before the start of exercise testing and then monitored continuously at each level of work load. Increased values for EBP were defined by sex and 10-year age-specific 80th percentile cut-off values during 100 W stage of exercise testing of participants with serum TSH levels within the reference range. The following exercise-associated variables were analyzed at the 100 W stage: increased ESBP, increased EDBP, and increased ESBP or EDBP. Additionally, increased differences between EBP and baseline resting blood pressure were considered as outcome variables.

Statistics

Data on quantitative characteristics are expressed as mean and standard deviation. Data on qualitative characteristics are expressed as absolute numbers and percent values. Bivariate comparisons between serum TSH level groups were made using Student's t-test (continuous data) or χ²-test (nominal data). Comparisons were performed separately against the group with low serum TSH (first tertile) within the reference range (0.25–0.65 mIU/L). Multivariable statistical analyses were performed using logistic regression analysis. Multivariable comparisons were made between all defined serum TSH groups relative to the second TSH group. Adjusted odds ratios (OR) and their 95% confidence intervals (CI) are provided. In sensitivity analyses linear regression models with EBP and serum TSH levels on the continuous scale were conducted. All analyses were controlled for sex, age, waist circumference, diabetes mellitus, smoking status, and antihypertensive medication. A value of p < 0.05 was considered statistically significant. Statistical analyses were performed using Stata 10 (Stata Corporation, College Station, TX).

Results

Baseline characteristics of the serum TSH level groups are presented in Table 1. Compared with the reference group of subjects with serum TSH levels in the lower reference range, subjects with increased serum TSH levels were more often women. Subjects with serum TSH levels in the higher reference range were younger and used antihypertensive medications less often relative to the reference group. Subjects with decreased serum TSH levels were more often ex-smokers than subjects of the reference group. Serum TSH level groups did not differ with respect to waist circumference, physical activity, systolic and diastolic blood pressure at rest, as well as hypertension and diabetes mellitus (Table 1).

Table 1.

Selected Characteristics of the Study Population

	Serum TSH levels (mIU/L)
Characteristics	<0.25 (n = 67)	0.25–0.65 (n = 454)	0.66–0.99 (n = 426)	1.00–2.12 (n = 421)	>2.12 (n = 70)
Sex (male)	32 (47.8%)	241 (53.1%)	215 (50.5%)	213 (50.6%)	26 (37.1%)^a
Age (year)	53.8 ± 11.3	52.5 ± 13.4	49.8 ± 12.3^a	48.3 ± 12.9^a	49.8 ± 13.5
Smoking status
Never smoker	21 (31.3%)	189 (41.6%)	194 (45.5%)	184 (43.7%)	33 (47.1%)
Ex-smoker	32 (47.8%)^a	133 (29.3%)	122 (28.6%)	135 (32.1%)	25 (35.7%)
Current smoker	14 (20.9%)	132 (29.1%)	110 (25.8%)	102 (24.2%)	12 (17.1%)
Waist circumference (mm)	919 ± 137	920 ± 132	913 ± 136	916 ± 140	899 ± 144
Physical activity	22 (32.8%)	168 (37.0%)	155 (36.4%)	177 (42.0%)	34 (48.6%)
Resting systolic blood pressure (mmHg)	130.7 ± 16.9	129.6 ± 18.3	129.2 ± 17.5	130.3 ± 17.4	130.1 ± 17.7
Resting diastolic blood pressure (mmHg)	81.7 ± 10.3	81.3 ± 9.4	81.7 ± 10.1	82.4 ± 9.9	82.0 ± 9.8
Resting hypertension	36 (53.7%)	192 (42.3%)	194 (45.5%)	177 (42.2%)	31 (44.3%)
Use of antihypertensive medication	24 (35.8%)	148 (32.6%)	120 (28.2%)	110 (26.1%)^a	26 (37.1%)
Diabetes mellitus	4 (6.0%)	29 (6.4%)	24 (5.6%)	27 (6.4%)	7 (10.0%)

Groups according to different serum TSH levels. Data are given as number (percentage) or mean ± standard deviation.

p < 0.05; χ²-test (nominal data) or Student's t-test (interval data). Comparisons were performed separately against the group with low serum TSH within the reference range (0.25–0.65 mIU/L).

TSH, thyrotropin.

In both sexes the unadjusted means of ESBP, EDBP, and the differences between EBP and resting blood pressure did not differ significantly between serum TSH level groups compared with the reference group of subjects with serum TSH levels in the lower reference range (Table 2).

Table 2.

Serum Thyrotropin Levels (mIU/L) and Exercise Blood Pressure (100 W) in Women and Men

	Serum TSH levels (mIU/L)
	<0.25	0.25–0.65	0.66–0.99	1.00–2.12	>2.12
Women	n = 35	n = 213	n = 211	n = 208	n = 44
Exercise
Systolic BP (mmHg)	172.8 ± 24.3	169.7 ± 27.1	169.4 ± 24.5	171.0 ± 27.3	172.5 ± 23.1
Diastolic BP (mmHg)	90.4 ± 11.9	90.2 ± 11.8	89.7 ± 12.7	88.9 ± 13.7	92.3 ± 11.9
Difference (exercise-rest)
Systolic BP (mmHg)	48.3 ± 20.3	53.0 ± 21.2	51.6 ± 19.6	51.0 ± 20.7	52.3 ± 21.7
Diastolic BP (mmHg)	4.3 ± 7.9	4.8 ± 10.4	3.9 ± 11.5	3.1 ± 11.5	5.2 ± 9.2
Men	n = 32	n = 241	n = 215	n = 213	n = 26
Exercise
Systolic BP (mmHg)	164.7 ± 22.7	164.0 ± 21.1	163.7 ± 24.2	161.8 ± 21.7	164.5 ± 27.5
Diastolic BP (mmHg)	84.9 ± 11.4	84.9 ± 11.9	86.4 ± 12.3	85.6 ± 12.4	85.3 ± 13.6
Difference (exercise-rest)
Systolic BP (mmHg)	42.3 ± 15.0	41.8 ± 17.2	41.2 ± 19.0	38.7 ± 17.3	38.1 ± 19.2
Diastolic BP (mmHg)	−0.5 ± 9.0	0.4 ± 11.2	−0.1 ± 9.0	−0.8 ± 9.0	−0.4 ± 13.7

Data are given as mean ± standard deviation. No result shows a significant p < 0.05; Student's t-test (interval data). Comparisons were performed separately against the group with low serum TSH within the reference range (0.25–0.65 mIU/L).

BP, blood pressure.

The 80th percentile values for ESBP according to age within the population of TSH reference range were higher in women (overall 192.4 mmHg) than in men (182.0 mmHg) and increased over the age groups in both sexes. The 80th percentile values for EDBP were almost constant over the age groups in both sexes and only slightly higher in women (overall 100.0 mmHg) than in men (95.0 mmHg). The increase in blood pressure from rest to exercise was also higher in women (overall 80th percentile systolic difference = 69.4 mmHg; diastolic difference = 12.0 mmHg) than in men (54.0 mmHg; 8.0 mmHg).

The fully adjusted multivariable logistic regression models did not reveal a significant and consistent relation between serum TSH levels and any EBP variable (ESBP, EDBP, and the difference between EBP and baseline blood pressure) when subjects with decreased or increased TSH as well as with higher serum TSH levels within the reference range were compared to those with serum TSH levels in the lower reference range (Table 3). Analyses adjusting for the interaction between gender and serum TSH level groups did not show different associations of serum TSH levels with EBP variables between men and women. Additional sensitivity analysis excluding subjects taken antihypertensive medications did not change the main findings substantially (Table 4).

Table 3.

The Relation Between Thyrotropin Levels and Exercise Blood Pressure (100 W) in the Total Sample

	Serum TSH levels (mIU/L)
Exercise BP	<0.25 (n = 67)	0.25–0.65 (n = 454)	0.66–0.99 (n = 426)	1.00–2.12 (n = 421)	>2.12 (n = 70)
Increased (>80th percentile)
Systolic BP	0.79 (0.37; 1.66)	1 (Ref.)	1.23 (0.87; 1.73)	1.24 (0.88; 1.76)	1.28 (0.67; 2.42)
Diastolic BP	0.62 (0.29; 1.30)	1 (Ref.)	0.82 (0.58; 1.16)	0.98 (0.70; 1.39)	1.13 (0.60; 2.12)
Diastolic or systolic BP	0.79 (0.43; 1.46)	1 (Ref.)	1.06 (0.78; 1.42)	1.30 (0.96; 1.75)	1.29 (0.74; 2.25)
Systolic BP difference	0.50 (0.22; 1.14)	1 (Ref.)	1.07 (0.76; 1.49)	0.94 (0.67; 1.33)	1.01 (0.52; 1.93)
Diastolic BP difference	0.75 (0.36; 1.53)	1 (Ref.)	0.92 (0.65; 1.29)	0.84 (0.59; 1.20)	0.89 (0.45; 1.74)
Diastolic or systolic BP difference	0.70 (0.38; 1.28)	1 (Ref.)	1.04 (0.78; 1.39)	0.91 (0.68; 1.23)	0.97 (0.55; 1.70)

Data are OR (95% confidence interval). No result shows a significant p < 0.05 logistic regression, model adjusted for sex, age, waist circumference, smoking status, diabetes mellitus, and antihypertensive medication.

Ref., reference group; OR, odds ratio.

Table 4.

The Relation Between Thyrotropin Levels and Exercise Blood Pressure (100 W) Among Subjects Without Antihypertensive Medication

	Serum TSH levels (mIU/L)
Exercise BP	<0.25 (n = 43)	0.25–0.65 (n = 306)	0.66–0.99 (n = 306)	1.00–2.12 (n = 311)	>2.12 (n = 44)
Increased (>80th percentile)
Systolic BP	1.62 (0.74; 3.52)	1 (Ref.)	1.28 (0.84; 1.95)	1.45 (0.96; 2.20)	1.08 (0.45; 2.59)
Diastolic BP	0.54 (0.20; 1.46)	1 (Ref.)	0.98 (0.65; 1.49)	1.06 (0.71; 1.60)	1.18 (0.53; 2.62)
Diastolic or systolic BP	1.09 (0.53; 2.24)	1 (Ref.)	1.09 (0.76; 1.56)	1.33 (0.93; 1.90)	1.14 (0.56; 2.34)
Systolic BP difference	0.72 (0.29; 1.81)	1 (Ref.)	1.11 (0.74; 1.68)	1.14 (0.76; 1.72)	0.75 (0.30; 1.88)
Diastolic BP difference	0.74 (0.29; 1.84)	1 (Ref.)	1.00 (0.67; 1.52)	0.87 (0.57; 1.33)	1.09 (0.49; 2.43)
Diastolic or systolic BP difference	0.80 (0.38; 1.71)	1 (Ref.)	1.15 (0.81; 1.63)	1.06 (0.74; 1.51)	0.99 (0.49; 2.02)

Data are OR (95% confidence interval). No result shows a significant p < 0.05 logistic regression; model adjusted for sex, age, waist circumference, smoking status, and diabetes mellitus.

In further sensitivity analyses we varied the definitions of ESBP and EDBP stepwise. Applying the definition of blood pressure values >80th percentile for higher exercise stages (116, 132, and 148 W) or using the 90th percentiles as cut-offs did also not reveal a statistically significant association between serum TSH levels and EBP. Likewise, analyses excluding subjects with a 5-year history of thyroid disease or current use of thyroid therapy drugs (ATC H03) did not significantly change our main results. In multivariable linear regression models with EBP and serum TSH levels on the continuous scale including resting blood pressure as an additional covariate, we also found no association between serum TSH levels and systolic EBP (β = 0.23, 95% CI −0.79; 1.26) or diastolic EBP (β = 0.04, 95% CI −0.52; 0.61) in the whole sample.

Discussion

In the present study, serum TSH levels were not related to EBP after consideration of major confounders. In particular, our hypothesis that high serum TSH levels might be related to increased ESBP and EDBP was not confirmed, even after exclusion of subjects with current antihypertensive medication. This is the first population-based study that investigated the association between thyroid function and EBP.

Although the present study is the largest investigation on this issue to date, some smaller studies (15,16) found similar results. In a case–control study (15), 42 patients with untreated overt hyperthyroidism had similar systolic and diastolic blood pressures during maximal exercise as 22 healthy controls. Moreover, no changes in systolic and diastolic blood pressure responses to exercise were observed in these patients after restoration of euthyroidism during 6 months' follow-up. Likewise, no effects on EBP were found in another, small interventional study (16) of 12 hyperthyroid patients after a treatment period of 10 months. In contrast, in a further study (17), 10 patients with long-term TSH-suppressive therapy with levothyroxine had a similar systolic blood pressure during maximal exercise but a higher systolic blood pressure during a submaximal exercise workload of 75 watt compared to a control group of 10 euthyroid subjects. These contrasting findings might be due to small sample sizes and limited control for potential confounders such as age, sex, body habitus, physical activity, and cardiac disease. Our design with a large sample size including more than 400 subjects in each of the three groups within the reference range of serum TSH levels (groups 2–4) would have allowed us to detect a relevant OR of 1.7 for increased EBP with a statistical power of 80% (p < 0.05). The groups with serum TSH levels below (group 1) and above the reference range (group 5) were substantially smaller resulting in a detectable OR of 2.6 for increased EBP with a statistical power of 80% (p < 0.05).

While two population-based studies (29,30) reported a modest association between high-normal serum TSH levels and resting blood pressure, our results are in agreement with other studies (31 –33) that did not find an association between subclinical hypothyroidism and blood pressure at rest. In a cross-sectional Chinese study (31) including 806 subjects with subclinical hypothyroidism and 5669 euthyroid controls, subclinical hypothyroidism was not associated with increased resting blood pressure. Likewise, in the cross-sectional Busselton Thyroid Study (32) including 105 subjects with subclinical hypothyroidism and 1859 euthyroid controls from Western Australia, subclinical hypothyroidism was not associated with hypertension. Two review articles (34,35) concluded that there is no conclusive evidence for a higher risk of hypertension in subjects with subclinical hypothyroidism. It is possible that we did not detect a modest association reported by the two large population-based studies (29,30) with 5872 and 30,728 subjects, respectively, because of our smaller study population. The clinical relevance of weak associations detected as statistically significant in very large studies, however, may be questionable.

Our findings also support other studies (31,33) that reported no association between subclinical hyperthyroidism and blood pressure at rest. In line with these findings, previous investigations of the SHIP population in a cross-sectional (36) and a longitudinal approach (37) with a median follow-up of 5 years revealed no association between subclinical hyperthyroidism and hypertension.

In designing our study and data analyses we had to make several decisions that may have affected our results. Thus, we opted for cycle ergometry as a means of physical exercise for our subjects since bicycling is common in Germany with 80% of all households owning at least one bicycle (38). Further, we chose to uniformly analyze the EBP data obtained during the 100 W stage of exercise testing assuming similar fitness levels of subjects in all five TSH groups. This decision was based on similar levels of self-reported physical activity in all groups (Table 1). Sex differences in biological work power were considered by using sex-specific definitions of increased EBP and by conducting additional sensitivity analyses for men at higher workloads. For reasons of statistical power, we used sex- and 10-year age-specific 80th percentile values for increased EBP variables. In sensitivity analyses we also considered 90th percentiles for cut-offs for increased EBP. As the value of EBP depends on the blood pressure at rest we considered blood pressure increase defined as the difference between blood pressure at rest and EBP as dependent variable. None of these additional analyses detected an association between serum TSH levels and EBP.

We used the TSH reference range of 0.25–2.12 mIU/L that was recently established for the study region—a previously iodine-deficient area (25). The distribution of serum TSH levels within a population strongly depends on the iodine supply (39). While the distribution curve is skewed toward lower levels in iodine-deficient regions, it is shifted toward higher levels in iodine-replete areas. Consequently, both lower and upper TSH reference values are lower in iodine-deficient areas than in regions with sufficient iodine supply (25,40,41). Thus, the reference values presented herein may be representative for populations from currently or previously iodine-deficient areas, but may be less generalizable for populations from iodine-replete regions.

Our study is limited by its cross-sectional design that precludes conclusions as to possible cause-and-effect relations. The strengths of our study include the population-based approach and the assessment of a large variety of potential confounders. Nevertheless, our results need confirmation by additional studies of similar size using a similar mode of exercise testing.

We conclude that serum TSH levels are not associated with EBP in the general population.

Footnotes

Acknowledgments

The Community Medicine Research net (CMR) of the University of Greifswald, Germany, encompasses several research projects that share data from the population-based Study of Health in Pomerania (SHIP; http://ship.community-medicine.de). The contributions to data collection made by field workers, technicians, interviewers, and computer assistants are gratefully acknowledged. The CMR is funded by the Federal Ministry of Education and Research (01ZZ9603, 01ZZ0103, 01ZZ0403, and 01ZZ0701); the Ministry of Cultural Affairs; and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. This work was further supported by the German Research Foundation (DFG Vo 955/5-1). Further, this work is part of the research project Greifswald Approach to Individualized Medicine (GANI_MED). The GANI_MED consortium is funded by the German Federal Ministry of Education and Research and as well as by the Ministry of Cultural Affairs of the German Federal State of Mecklenburg–West Pomerania (03IS2061A).

Disclosure Statement

The authors declare that no competing financial interests exist.

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