Thyroid Stimulating Hormone
THYROID HORMONES INFLUENCE the cardiovascular system (1), and thyroid dysfunction may increase the risk of cardiovascular disease (2). Previous studies have shown that both hypo- and hyperthyroid disease may increase the risk of hypertension (2–5) and that hypertension related to hypothyroidism may be reversed after T4 treatment (6–8). Subclinical hypothyroid function, characterized by thyroid hormones within the reference range combined with elevated TSH, has been associated with higher diastolic blood pressure (9), and after T4 treatment, it has been demonstrated that diastolic (10) and mean arterial pressure (11) may be reduced. However, others have failed to demonstrate any association between blood pressure and subclinical hypo- (12) or hyperthyroidism (13).
In people with no apparent thyroid dysfunction, one study showed lower thyroid function among people with hypertension (14). Consistent with this finding, the results of two recent population-based studies (13, 15) indicate a positive association between TSH within the reference range and systolic and diastolic blood pressure.
The association between TSH within the reference range and blood pressure is insufficiently studied. In a study of more than 30,000 individuals, we therefore examined whether concentrations of TSH within the reference range are related to systolic and diastolic blood pressure, pulse pressure, and the prevalence of hypertension.
Subjects and Methods
Between 1995 and 1997, all inhabitants 20 yr of age or older in Nord-Trøndelag County in Norway were invited to participate in the Nord-Trøndelag Health Study (HUNT). A total of 92,936 individuals were eligible to participate, and 66,140 (71.2%) attended. The study has been described in detail elsewhere (16). Briefly, the participants were asked to complete a self-administered questionnaire, which included eight thyroid-specific questions (17). By self-report, information on health and lifestyle factors was also collected as well as history of diabetes mellitus, angina pectoris, myocardial infarction, and stroke and information on the use of antihypertensive medication.
Blood pressure was measured by specially trained nurses or technicians using a Dinamap 845XT (Critikon, Tampa, FL) based on oscillometry. Cuff size was adjusted after measuring the arm circumference. After 2 min rest, the blood pressure was automatically measured three times at 1-min intervals. In this study, we used the mean value of the second and third measurement of systolic and diastolic blood pressure. Pulse pressure was calculated as the difference between systolic and diastolic blood pressure.
A nonfasting venous blood sample was drawn from each individual. Analysis of serum TSH was carried out in subsamples of the population, including all women older than 40 yr of age and 50% of men older than 40 yr of age. In addition, TSH was measured in 5% random samples of men and women 20–40 yr of age. In total, 34,851 individuals from these samples were selected for TSH analysis.
Nord-Trøndelag County is located in the middle part of Norway and is characterized by a stable and homogenous population (16). The prevalence of thyroid disease has been previously estimated (17). Briefly, 0.6% of men and 2.5% of women had hyperthyroidism, whereas 0.9% of men and 4.8% of women had hypothyroidism, based on self-report. Among people older than 40 yr of age, 19.6% reported current or previous use of antihypertensive medication. The Norwegian population is generally considered to have sufficient iodine intake (18).
Serum concentration of TSH was analyzed at the Hormone Laboratory, Aker University Hospital, Oslo, using DELFIA hTSH Ultra (sensitivity 0.03 mU/liter and total analytical variation < 5%; Wallac Oy, Turku, Finland). Reference ranges for TSH from this population have been published previously (17). Based on these results, the reference range for TSH in the present study was defined as 0.50–3.5 mU/liter.
Among the 34,851 individuals who were selected for TSH analysis, 30,728 were included in the present study. Exclusion criteria were previously known thyroid disease (n = 2904) and missing information on TSH, blood pressure, use of antihypertensive medication, or smoking status (n = 1219). In the analyses related to systolic and diastolic blood pressure and pulse pressure, we further excluded those who reported current or previous use of antihypertensive medication (n = 5702).
The association between TSH and blood pressure was analyzed using general linear models. Within the reference range of TSH, we calculated mean systolic and diastolic blood pressure and pulse pressure for six categories of TSH (0.50–0.99, 1.00–1.4, 1.5–1.9, 2.0–2.4, 2.5–2.9, and 3.0–3.5 mU/liter). We also analyzed the association between TSH and blood pressure by calculating partial-regression coefficients, with corresponding 95% confidence intervals (CI). The partial-regression coefficients are presented as the average increase in blood pressure per milliunit per liter increase in TSH. Results from the analyses of log-transformed and nontransformed blood pressure were nearly identical, and we therefore present the nontransformed results.
We stratified the association of TSH and blood pressure by sex and age (age groups younger than 50 yr of age, 50–69 yr, and 70 yr and older). Similarly, we assessed whether the association of TSH and blood pressure differed between current smokers, former smokers, and never-smokers and between overweight and normal weight individuals, using body mass index (BMI; weight divided by the squared value of height) of 25.0 kg/m2 as cutoff.
In a logistic regression model, we calculated odds ratios for hypertension for the six categories of TSH within the reference range, using TSH 0.50–0.99 mU/liter as reference group. Hypertension was defined as systolic blood pressure higher than 140 mm Hg and/or diastolic blood pressure higher than 90 mm Hg and/or current or previous use of antihypertensive medication.
In a separate analysis, we studied the association with blood pressure also including TSH concentrations outside the reference range. We calculated mean systolic and diastolic blood pressure and pulse pressure for five categories of TSH [less than 0.10, 0.10–0.49, 0.50–3.5 (reference range), 3.6–9.9, and 10.0 mU/liter and higher]. We compared the blood pressures for each category of TSH outside the reference range with mean blood pressures corresponding to TSH within the reference range. In a logistic regression model, we calculated odds ratios for hypertension for these categories of TSH, using TSH 0.50–3.5 mU/liter as reference group.
The data were analyzed using the Statistical Package for the Social Sciences (SPSS), version 14.0 for Windows (SPSS Inc., Chicago, IL).
The HUNT study is a collaborative effort of the Faculty of Medicine, the Norwegian University of Science and Technology, the Norwegian Institute of Public Health, and Nord-Trøndelag County Council. The study was approved by the regional committee for medical research ethics and by the Norwegian Data Inspectorate.
Within the reference range of TSH (0.50–3.5 mU/liter), there was a linear increase in systolic and diastolic blood pressure with increasing concentration of TSH (Figs. 1 and 22). The average increase in systolic blood pressure per milliunit per liter increase in TSH was 2.0 mm Hg (95% CI 1.4–2.6 mm Hg) in men and 1.8 mm Hg (95% CI 1.4–2.3 mm Hg) in women. Similarly, the average increase in diastolic blood pressure per milliunit per liter increase in TSH was 1.6 mm Hg (95% CI 1.2–2.0 mm Hg) in men and 1.1 mm Hg (95% CI 0.8–1.3 mm Hg) in women. In women, the average increase in pulse pressure was 0.8 mm Hg (95% CI, 0.5–1.1 mm Hg) per milliunit per liter increase in TSH, but in men, TSH was not significantly associated with pulse pressure. These results were adjusted for age and smoking status. Additional adjustment for arm circumference and the prevalence of diabetes mellitus, angina pectoris, myocardial infarction, or stroke did not substantially influence the results.