Diagnosis of subclinical central hypothyroidism in patients with hypothalamic–pituitary disease by Doppler echocardiography

in European Journal of Endocrinology

Objective

The diagnosis of subclinical central hypothyroidism in hypothalamic–pituitary patients cannot be established by serum markers of thyroid hormone action. Myocardial function by echocardiography has been shown to reflect thyroid hormone action in primary thyroid dysfunction. We evaluated the performance of echocardiography in diagnosing subclinical central hypothyroidism.

Design

Cross-sectional and before and after.

Methods

Echocardiography and serum thyroid hormones were assessed in overt primary (n=20) and central (n=10) hypothyroidism, subclinical primary hypothyroidism (n=10), hypothalamic–pituitary disease with normal free thyroxine (FT4; n=25), and controls (n=28). Receiver operating characteristic (ROC) curves were generated using overt hypothyroidism patients and selected cut-off values were applied to detect both primary and central subclinical hypothyroidism. After levothyroxine (l-T4) intervention, patients were echocardiographically reevaluated at predefined targets: normal thyrotropin (TSH) in primary hypothyroidism, normal FT4 in overt central hypothyroidism, and higher than pretreatment FT4 in echo-defined subclinical central hypothyroidism.

Results

Parameters with highest areas under the ROC curves (area under the curve (AUC) ≥0.94) were as follows: isovolumic contraction time (ICT), ICT/ejection time (ET), and myocardial performance index. Highest diagnostic accuracy (93%) was obtained when at least one parameter was increased (positive and negative predictive values: 93%). Hypothyroidism was echocardiographically diagnosed in eight of ten patients with subclinical primary hypothyroidism and in 14 of 25 patients (56%) with hypothalamic–pituitary disease and normal serum FT4. Echocardiographic abnormalities improved significantly after l-T4 and correlated (0.05<P<0.001) with changes in FT4 (−0.62<r<−0.55) and TSH (0.63<r<0.68) in primary hypothyroidism and with FT4 in central hypothyroidism (−0.72<r<−0.50).

Conclusion

Echocardiography can be useful in diagnosing subclinical central hypothyroidism in patients with hypothalamic–pituitary disease.

Abstract

Objective

The diagnosis of subclinical central hypothyroidism in hypothalamic–pituitary patients cannot be established by serum markers of thyroid hormone action. Myocardial function by echocardiography has been shown to reflect thyroid hormone action in primary thyroid dysfunction. We evaluated the performance of echocardiography in diagnosing subclinical central hypothyroidism.

Design

Cross-sectional and before and after.

Methods

Echocardiography and serum thyroid hormones were assessed in overt primary (n=20) and central (n=10) hypothyroidism, subclinical primary hypothyroidism (n=10), hypothalamic–pituitary disease with normal free thyroxine (FT4; n=25), and controls (n=28). Receiver operating characteristic (ROC) curves were generated using overt hypothyroidism patients and selected cut-off values were applied to detect both primary and central subclinical hypothyroidism. After levothyroxine (l-T4) intervention, patients were echocardiographically reevaluated at predefined targets: normal thyrotropin (TSH) in primary hypothyroidism, normal FT4 in overt central hypothyroidism, and higher than pretreatment FT4 in echo-defined subclinical central hypothyroidism.

Results

Parameters with highest areas under the ROC curves (area under the curve (AUC) ≥0.94) were as follows: isovolumic contraction time (ICT), ICT/ejection time (ET), and myocardial performance index. Highest diagnostic accuracy (93%) was obtained when at least one parameter was increased (positive and negative predictive values: 93%). Hypothyroidism was echocardiographically diagnosed in eight of ten patients with subclinical primary hypothyroidism and in 14 of 25 patients (56%) with hypothalamic–pituitary disease and normal serum FT4. Echocardiographic abnormalities improved significantly after l-T4 and correlated (0.05<P<0.001) with changes in FT4 (−0.62<r<−0.55) and TSH (0.63<r<0.68) in primary hypothyroidism and with FT4 in central hypothyroidism (−0.72<r<−0.50).

Conclusion

Echocardiography can be useful in diagnosing subclinical central hypothyroidism in patients with hypothalamic–pituitary disease.

Introduction

Central hypothyroidism is a frequent disorder in patients with hypothalamic–pituitary disease. It results from decreased stimulation of an otherwise normal thyroid gland by a decreased and/or biologically less active thyrotropin (TSH) (1, 2). Risk factors for central hypothyroidism include large sellar lesions, previous surgery, radiotherapy, and other pituitary hormone deficiencies. In practice, the diagnosis of central hypothyroidism relies on a low serum free thyroxine (FT4) with decreased, normal, or slightly elevated serum TSH (3). However, a low serum FT4 is a highly specific but insensitive marker of hypothyroidism, whereas several serum markers of thyroid hormone action and the response of TSH to its releasing hormone have shown low diagnostic sensitivity (4, 5).

The cardiovascular system is a major target of thyroid hormone, which influences cardiac function both directly and indirectly via changes in peripheral vascular resistance and circulating volume (6). Noninvasive evaluation of myocardial function, both in animals and humans, has shown opposite abnormalities in systolic time intervals in primary hypothyroidism and hyperthyroidism that can be reversed by appropriate therapy (7, 8, 9). In primary hypothyroidism, systolic time intervals are typically lengthened and decreased after T4 replacement in correlation with changes in thyroid hormones (10).

Formerly, assessment of systolic intervals was cumbersome, involving simultaneous recordings of electrocardiogram, phonocardiogram, and carotid pulse tracing (11). Currently, Doppler echocardiography is a simple and widely available method that allows reliable evaluation of cardiac structure and function (12). Previous echocardiographic studies have demonstrated alterations in systolic and diastolic parameters in both overt and subclinical primary hypothyroidism (13, 14, 15, 16, 17). In this study, we tested the hypothesis that selected parameters of myocardial function by echocardiography could be useful in diagnosing subclinical central hypothyroidism in patients with hypothalamic–pituitary disease and normal serum FT4 levels.

Materials and methods

Patients and controls

The study included 35 patients with hypothalamic–pituitary disease (ten macroprolactinomas, six craniopharyngiomas, six idiopathic hypopituitarism, five Sheehan's syndrome, five nonfunctioning pituitary macroadenomas, one sarcoidosis, one Langerhans cell histiocytosis, and one brain traumatic injury), irrespective of previous surgery, radiotherapy, pharmacological treatment, or hormone replacement therapy (including T4), and 30 patients with primary hypothyroidism, diagnosed by high serum TSH, due to Hashimoto's thyroiditis (n=28) or previous thyroidectomy. Patients were carefully evaluated to exclude hypertension or coexisting primary cardiac disease which could interfere with the echocardiographic results; patients with acromegaly or Cushing's disease were not included due to the frequent association with hypertension and/or cardiac hypertrophy.

Patients with hypothalamic–pituitary disease and low serum FT4 were classified as overt central hypothyroidism; patients with primary thyroid disease, high serum TSH, and low serum FT4 as overt primary hypothyroidism; and patients with primary thyroid disease, high TSH, and normal serum FT4 as subclinical primary hypothyroidism. Patients with hypothalamic–pituitary disease and normal serum FT4 were further classified as subclinical central hypothyroidism or euthyroidism according to echocardiography.

Twenty-eight healthy subjects were included as controls. Patients and controls were studied after informed consent and study approval by the Ethic Committee.

Study design

Baseline assessment

Patients were submitted to physical exam and baseline hormonal and echocardiographic assessment. Fasting morning blood collection for hormone measurements and echocardiographic evaluation were performed on the same day.

T4 intervention

Patients with overt primary hypothyroidism, overt central hypothyroidism, subclinical primary hypothyroidism, and hypothalamic–pituitary disease with normal serum FT4 and echocardiographically defined hypothyroidism (subclinical central hypothyroidism) were started on levothyroxine (l-T4; 1.0–1.7 μg/kg of body weight per day) and/or increased by 25 μg every 4–6 weeks until reaching the following: normal serum TSH in overt and subclinical primary hypothyroidism; normal serum FT4 in overt central hypothyroidism (mid-range/high-normal); and a higher than baseline serum FT4 (mid-range/high-normal) in subclinical central hypothyroidism. Patients were monitored for signs and symptoms of thyrotoxicosis; patients with hypothalamic–pituitary disease were also monitored through serum triiodothyronine (T3) measurements. Echocardiography was repeated when hormonal targets were reached. Replacement of other hormone deficiencies was kept constant for at least 6 months before and during the study.

Hormone assays

Serum TSH was measured in duplicate by an in-house sensitive third-generation immunofluorometric assay (intra- and interassay coefficients of variation (CV), 4 and 6% respectively; sensitivity, 0.03 mU/l; and normal reference values: 0.4–5.0 mU/l). Serum FT4 was measured in duplicate by an immunofluorometric assay (Delfia; Wallac Oy, Turku, Finland; intra- and interassay CV, 4.4 and 6.1% respectively; sensitivity, 0.16 ng/dl; and normal reference values: 0.7–1.54 ng/dl). Serum T3 (total) was measured by an immunofluorometric assay (Delfia; Wallac Oy; intra- and interassay CV, 3.0%; sensitivity, 20 ng/dl; and normal reference values, 80–210 ng/dl).

Echocardiographic assessment

A complete two-dimensional Doppler echocardiographic examination was performed using an ATL-5000 ultrasound machine (Philips, Andover, MA, USA) with a 2.0–2.5 MHz transducer according to standard technique (12). Left ventricle ejection fraction was obtained by Teichholz method (18). Assessment of the myocardial performance index (MPI) (19), defined as the sum of isovolumic contraction time (ICT) and isovolumic relaxation time divided by left ventricle ejection time (ET), was carried out by sequential recording of the mitral inflow (from the apical four-chamber view with the pulsed wave Doppler sample volume positioned at the tips of the mitral leaflets during diastole) and of the left ventricle outflow tract (from the apical long axis view with the sample volume positioned just below the aortic valve). Measurements of Doppler tracings were performed with simultaneous electrocardiogram recording in five consecutive heart beats and expressed as the mean value as previously described (20). Measurements were made by a single observer (FCD) uninformed of patients' data.

Statistical analysis

Comparisons between more than two groups were made by ANOVA, followed by paired or unpaired parametric or nonparametric post hoc tests. Correlations were calculated using Pearson's (r) or Spearman's (rS) coefficients. Comparison between frequencies were calculated by χ2 or Fisher's exact test. Receiver operating characteristic (ROC) curves were generated using selected echocardiographic parameters from controls and patients with biochemical overt hypothyroidism according to currently accepted diagnostic gold standards: low serum FT4 with low, normal, or slightly increased TSH in patients with hypothalamic–pituitary disease for central hypothyroidism; and low serum FT4 with high TSH in patients with primary thyroid disease. Echocardiographic parameters from patients with subclinical primary hypothyroidism or hypothalamic–pituitary disease with normal serum FT4 were not used to generate the ROC curves and served as application groups. P values <0.05 were considered significant. Statistical analyses were performed using GraphPad Prism version 5.00 for Windows (GraphPad Software Inc., San Diego, CA, USA, www.graphpad.com). Data were expressed as mean±s.d.

Results

No significant differences were found in age, sex distribution, heart rate, or blood pressure between patients with overt primary hypothyroidism, overt central hypothyroidism, subclinical primary hypothyroidism, hypothalamic–pituitary disease with normal serum FT4, and controls (Table 1).

Table 1

Baseline clinical and hormonal characteristics of controls and patients with overt primary hypothyroidism, overt central hypothyroidism, subclinical primary hypothyroidism, and hypothalamic–pituitary disease with normal FT4 levels. Plus–minus values are means±s.d.

Controls (n=28)Overt primary hypothyroidism (n=20)Overt central hypothyroidism (n=10)Subclinical primary hypothyroidism (n=10)Hypothalamic–pituitary normal FT4 (n=25)P valuea
Age (years)35.8±8.840.7±13.831.0±9.835.7±8.833.0±11.00.11
Female sex (no.)161658130.13
Heart rate (bpm)67±966±1162±870±1365±110.74
Systolic BP (mmHg)118±11117±12121±9115±8117±120.80
Diastolic BP (mmHg)77±1078±1081±975±778±90.67
Serum FT4 (ng/dl)b1.02±0.150.29±0.13c0.45±0.14c0.94±0.240.95±0.14<0.001
Serum TSH (mU/l)1.70±1.0397.17±53.75c3.26±3.3514.28±5.59c0.99±1.08<0.001

BP, blood pressure; FT4, free thyroxine; TSH, thyrotropin.

P values are for the comparisons between all groups by ANOVA, except for sex distribution (χ2 test).

To convert serum FT4 from nanograms per deciliter to picomole per liter multiply by 12.87.

P value <0.05 for comparisons between patients and controls (Dunnett's or Dunn's multiple comparison test).

Baseline assessment in overt hypothyroidism

As expected, serum FT4 was significantly lower in both overt primary and overt central hypothyroidism as compared with controls, and serum TSH was significantly higher in overt primary hypothyroidism but not in overt central hypothyroidism as compared with controls (Table 1).

As shown in Table 2, left ventricle ejection fraction, MPI, ICT, and ICT/ET ratio were significantly different from controls in both overt primary and overt central hypothyroidism. Left ventricle ET and isovolumic relaxation time were significantly different only in overt primary hypothyroidism. No significant differences in ventricular dimensions and left ventricle mass index were observed (data not shown). One patient with primary hypothyroidism presented mild pericardial effusion.

Table 2

Baseline echocardiographic parameters in patients with overt primary hypothyroidism, overt central hypothyroidism, and controls. Plus–minus values are means±s.d.

Controls (n=28)Overt primary hypothyroidism (n=20)Overt central hypothyroidism (n=10)P valuea
Left ventricle ejection fraction0.67±0.040.63±0.05b0.61±0.05b0.003
MPI0.40±0.050.65±0.15b0.51±0.10b<0.001
ICT (ms)39±1074±23b75±24b<0.001
ICT/ET ratio0.13±0.030.28±0.11b0.25±0.08b<0.001
ET (ms)298±16271±24b298±25<0.001
Isovolumic relaxation time (ms)80±1399±23b77±16<0.001

ICT, isovolumic contraction time; ICT/ET, ICT/ejection time; MPI, myocardial performance index.

P values are for the comparisons between all groups by ANOVA.

P value <0.05 for comparisons between patients and controls (Dunnett's multiple comparison test).

ROC curves analysis of echocardiographic parameters in the diagnosis of hypothyroidism

Figure 1 shows the echocardiographic parameters with the highest areas under the ROC curves. The chosen cut-off values for the diagnosis of hypothyroidism were the following: ICT >53 ms (sensitivity, 83%; confidence interval (CI), 65–94%; specificity, 96%; CI, 82–100%); ICT/ET ratio >0.18 (sensitivity, 83%; CI, 65–94%; specificity, 96%; CI, 82–100%); and MPI >0.46 (sensitivity, 90%; CI, 74–98%; specificity, 93%; CI, 77–99%). For ICT and ICT/ET ratio, cut-off values showed identical accuracy, positive, and negative predictive values of 90, 96, and 84% respectively. For MPI, accuracy, positive, and negative predictive values were 91, 93, and 90% respectively. A highest diagnostic accuracy of 93% was obtained when at least one parameter was increased (positive and negative predictive values, 93%). Intra- and interobserver variability (percent of mean value) for MPI, ICT, and ICT/ET ratio were 2.7±2.2, 5.9±5.9, 4.1±2.9, 6.3±7, and 9.1±5.6, 9.4±4% respectively.

Figure 1
Figure 1

ROC curves and the corresponding AUC for (A) the isovolumic contraction time (ICT), (B) the ratio between ICT and ejection time, and (C) the myocardial performance index (MPI) as markers of hypothyroidism in patients with overt primary and central hypothyroidism. An AUC value of 0.5 is no better than expected by chance and a value of 1.0 indicates a perfect diagnostic marker. Arrows indicate the chosen diagnostic cut-off values.

Citation: European Journal of Endocrinology 166, 4; 10.1530/EJE-11-0907

Echocardiographic diagnosis of hypothyroidism in patients with normal serum FT4

Serum FT4 levels in patients with subclinical primary hypothyroidism and in patients with hypothalamic–pituitary disease with normal FT4 were not significantly different from controls. As expected, serum TSH levels were significantly higher in subclinical primary hypothyroidism, but not in hypothalamic–pituitary disease with normal FT4, as compared with controls (Table 1). No significant differences in ventricular dimensions and left ventricle mass indexes were observed among these groups (data not shown).

Subclinical primary hypothyroidism

As shown in Table 3, all three diagnostic echocardiographic parameters were significantly increased in subclinical primary hypothyroidism. Eight of ten patients with subclinical primary hypothyroidism were also diagnosed as hypothyroid by echocardiography (Fig. 2).

Table 3

Baseline echocardiographic parameters in patients with subclinical primary hypothyroidism, hypothalamic–pituitary disease with normal serum FT4 and controls. Plus–minus values are means±s.d.

Controls (n=28)Subclinical primary hypothyroidism (n=10)Hypothalamic–pituitary normal FT4 (n=25)P valuea
Left ventricle ejection fraction 0.67±0.040.67±0.040.62±0.03b<0.001
MPI0.40±0.050.48±0.09b0.43±0.070.005
ICT (ms)39±1053±11b55±17b<0.001
ICT/ET ratio0.13±0.030.19±0.04b0.18±0.06b<0.001
ET (ms)298±16288±27302±160.12
Isovolumic relaxation time (ms)80±1384±1678±160.50

FT4, free thyroxine; ICT, isovolumic contraction time; ICT/ET, ICT/ejection time; MPI, myocardial performance index.

P values are for the comparisons between all groups by ANOVA.

P value <0.05 for comparisons between patients and controls (Dunnett's multiple comparison test).

Figure 2
Figure 2

Selected diagnostic echocardiographic parameters in patients with overt and subclinical primary hypothyroidism, overt central hypothyroidism, hypothalamic–pituitary disease with normal serum free thyroxine (FT4), and controls. Each circle represents one patient. Dashed horizontal lines indicate the chosen cut-off values: 53 ms for the ICT, 0.18 for the ratio between ICT and ET, and 0.46 for the MPI. Patients with hypothalamic–pituitary disease and normal FT4 that had at least one of the three parameters above the cut-off value were diagnosed as subclinical central hypothyroidism and are represented by solid circles.

Citation: European Journal of Endocrinology 166, 4; 10.1530/EJE-11-0907

Hypothalamic–pituitary disease with normal serum FT4

As shown in Table 3, both ICT and ICT/ET ratio were significantly increased, and left ventricle ejection fraction was significantly decreased in hypothalamic–pituitary disease with normal serum FT4.

Hypothyroidism was diagnosed by echocardiography in 14 of 25 patients (56%) with hypothalamic–pituitary disease and normal serum FT4 (Fig. 2). These patients were younger than patients echocardiographically defined as euthyroid (28±8 vs 40±11 years, P=0.004, t-test), but no significant differences were found in sex, heart rate, blood pressure, serum FT4 and T3, prevalence of untreated GH deficiency, or other pituitary hormone deficiencies (Table 4).

Table 4

Clinical and hormonal parameters in patients with or without echocardiographically defined subclinical central hypothyroidism. Plus–minus values are means±s.d.

Subclinical central hypothyroidism
Yes (n=14)No (n=11)P valuea
Age (years)28±840±110.004
Female sex (no.)670.43
Heart rate (bpm)65±964±90.79
Systolic blood pressure (mmHg)118±14117±110.85
Diastolic blood pressure (mmHg)79±876±100.41
Serum FT4 (ng/dl)b0.96±0.140.95±0.150.87
Serum T3 (ng/dl)c114±25105±90.27
Untreated GH deficiency (no.)990.41
Hypogonadism (no.)571
Glucocorticoid deficiency (no.)361

FT4, free thyroxine; T3, triiodothyronine.

P values for comparisons between groups by unpaired t-test (age, heart rate, blood pressure, serum FT4, and T3) or Fisher's exact test (sex, untreated GH deficiency, hypogonadism, and glucocorticoid deficiency).

To convert serum FT4 from nanograms per deciliter to picomole per liter multiply by 12.87.

To convert serum T3 from nanograms per deciliter to nanomole per liter multiply by 0.0154.

Baseline echocardiographic and hormonal correlations

In primary hypothyroidism, as expected, the highest correlation was found between serum TSH and serum FT4 (rS=−0.70, P<0.001); serum TSH was also correlated with ICT (rS=0.53, P=0.003), ICT/ET ratio (rS=0.54, P=0.002), and MPI (rS=0.55, P=0.002). FT4 correlated with ICT (rS=−0.54, P=0.002), ICT/ET ratio (rS=−0.55, P=0.002), and MPI (rS=−0.62, P<0.001).

In central hypothyroidism, diagnosed either biochemically or echocardiographically, the highest correlation was between serum FT4 and the MPI (r=−0.79, P<0.001); serum FT4 also correlated with ICT (r=−0.52, P=0.02) and ICT/ET ratio (r=−0.60, P=0.006).

Changes after T4 intervention

Fifty-four patients met the criteria for T4 intervention; 43 completed the study (Fig. 3 and Table 5). Two thyroidectomized patients were not included because TSH levels were suppressed after l-T4 and four patients were not available on recall. Five patients were excluded due to poor compliance. No patient developed clinical signs and/or symptoms of excessive T4 replacement.

Figure 3
Figure 3

Diagnostic parameters before and after thyroxine (T4) intervention in patients with overt primary, overt central, subclinical primary, and subclinical central hypothyroidism. Box and whisker plots show the 10th, 25th, 50th (median), 75th, and 90th percentile values for the isovolumic contraction time (ICT), the ratio between ICT and ejection time (ET), and the myocardial performance index, before (gray boxes) and after (white boxes) T4 intervention in patients with primary and central overt and subclinical hypothyroidism. *P<0.05, paired t-test. Black dots represent outliers. Values in parentheses are the numbers of patients in each group.

Citation: European Journal of Endocrinology 166, 4; 10.1530/EJE-11-0907

Table 5

Clinical, hormonal, and echocardiographic parameters before and after T4 intervention in patients with overt primary hypothyroidism, overt central hypothyroidism, subclinical primary hypothyroidism, and echocardiographically defined subclinical central hypothyroidism. Plus–minus values are means±s.d.

Overt primary hypothyroidism (n=15)Overt central hypothyroidism (n=9)Subclinical primary hypothyroidism (n=9)Subclinical central hypothyroidism (n=10)
T4 interventionBeforeAfterBeforeAfterBeforeAfterBeforeAfter
Heart rate (bpm)67±1169±1162±868±967±1472±1165±1172±9.6
Systolic BP (mmHg)117±11117±12122±10118±19117±7114±11121±15128±10
Diastolic BP (mmHg)77±1077±782±978±1377±577±681±888±4
Serum FT4 (ng/dl)a0.29±0.121.14±0.18b0.45±0.151.22±0.43b0.96±0.241.14±0.18b0.96±0.151.38±0.22b
Serum T3 (ng/dl)cNANA82±26127±29bNANA103±21140±31b
Serum TSH (mU/l)100.30±59.102.43±1.34b3.61±3.34NA13.0±4.132.28±1.54b0.89±1.17NA
Left ventricle ejection fraction0.62±0.050.66±0.04b0.61±0.050.63±0.040.67±0.040.67±0.050.64±0.030.64±0.05
MPI0.67±0.050.44±0.10b0.53±0.080.38±0.08b0.48±0.090.40±0.070.48±0.060.39±0.09b
ICT (ms)76±2145±23b79±2138±13b51±840±13b72±852±19b
ICT/ET ratio0.30±0.120.16±0.10b0.27±0.070.13±0.04b0.18±0.030.14±0.04b0.23±0.030.17±0.06b
ET (ms)266±24285±26b296±26293±20288±28287±18305±0302±17
Isovolumic relaxation  time (ms)99±2381±20b78±1673±1685±1675±17b73±1567±18

BP, blood pressure; FT4, free thyroxine; T3, triiodothyronine; TSH, thyrotropin; NA, not applicable; ICT, isovolumic contraction time; ICT/ET, ICT/ejection time; MPI, myocardial performance index.

To convert serum FT4 from nanograms per deciliter to picomole per liter multiply by 12.87.

P value <0.05 for comparisons between parameters before and after thyroxine intervention (paired t-test).

To convert serum T3 from nanograms per deciliter to nanomole per liter multiply by 0.0154.

l-T4 significantly increased serum FT4 in all groups, but did not significantly change heart rate and blood pressure. Mean serum TSH decreased to the normal range in primary hypothyroidism and serum T3 increased within the normal range in all patients with hypothalamic–pituitary disease.

Overt hypothyroidism

After treatment, all diagnostic echocardiographic parameters decreased significantly in overt hypothyroidism. In overt primary hypothyroidism, these three parameters decreased in all 15 patients and each one reached values lower than the mean+2 s.d. of control subjects in 73–77% of patients. In overt central hypothyroidism, these parameters also decreased in all nine patients, and all but one of each diagnostic parameter decreased below mean+2 s.d. of controls. After T4, echocardiographic measurements below the mean−2 s.d. were observed in four of 24 patients.

Subclinical hypothyroidism

T4 intervention significantly decreased all diagnostic echocardiographic parameters in both subclinical primary and subclinical central hypothyroidism, and corrected 28 of 29 (97%) abnormal parameters in subclinical primary hypothyroidism, and 21 of 29 (72%) in subclinical central hypothyroidism. Low echocardiographic measurements (<mean−2 s.d.) were observed in two of 18 patients.

Echocardiographic and hormonal correlations after T4

Significant correlations were found between changes (Δ=posttreatment minus pretreatment values) in serum thyroid hormones and changes in diagnostic echocardiographic parameters in patients with primary and central hypothyroidism (overt and subclinical).

In primary hypothyroidism, ΔTSH correlated (0.01<P<0.001) with ΔFT4 (rS=−0.67), ΔICT (rS=0.63), ΔICT/ET ratio (rS=0.68), and ΔMPI (rS=0.66); ΔFT4 correlated (0.01<P<0.001) with ΔICT (r=−0.60), ΔICT/ET ratio (rS=−0.55), and ΔMPI (rS=−0.62).

In central hypothyroidism, ΔFT4 correlated (0.05<P<0.01) with ΔICT (r=−0.51), ΔICT/ET ratio (r=−0.50), and ΔMPI (rS=−0.72).

As shown in Fig. 4, when all patients with both primary and central overt and subclinical hypothyroidism were analyzed together, ΔFT4 correlated significantly with ΔICT (r=−0.54), ΔICT/ET ratio (r=−0.64), and ΔMPI (rS=−0.70).

Figure 4
Figure 4

Correlations between changes (Δ=posttreatment minus pretreatment values) in serum FT4 and each echocardiographic diagnostic parameter after levothyroxine in patients with primary (solid circles) and central (open circles) overt and subclinical hypothyroidism (n=42). Slanting lines represent linear regression lines between parameters. FT4, free thyroxine; ICT, isovolumic contraction time; ICT/ET, ICT/ejection time ratio; MPI, myocardial performance index.

Citation: European Journal of Endocrinology 166, 4; 10.1530/EJE-11-0907

Discussion

In this study, we have shown that echocardiography is a simple and accurate method to detect tissue hypothyroidism, which was especially useful in diagnosing subclinical central hypothyroidism in patients with hypothalamic–pituitary disease and normal serum FT4. As opposed to subclinical primary hypothyroidism, which is easily diagnosed by increased serum TSH with normal serum FT4 levels, the diagnosis of subclinical central hypothyroidism has been elusive in clinical practice. Selected myocardial function parameters including the systolic time intervals – ICT and ICT/ET ratio – and the MPI, which are largely independent of heart rate (11, 21), have shown high diagnostic accuracy as demonstrated by ROC curve analysis using only patients with overt central and primary hypothyroidism and controls. When applied to patients with subclinical primary hypothyroidism, these markers were in diagnostic agreement with serum TSH levels in 80% of cases. In patients with hypothalamic–pituitary disease and normal serum FT4 who were considered at risk for subclinical central hypothyroidism, these markers indicated tissue hypothyroidism in 56% of patients. The specificity of these measurements to detect tissue thyroid hormone deficiency was further supported by their reversal or improvement after T4, without any clinical or biochemical sign of excessive T4 replacement, in both biochemical and echocardiographically defined hypothyroidism.

The pathophysiology of disturbed myocardial performance in hypothyroidism, as reflected by alterations in several echocardiographic parameters, involves both direct and indirect effects of thyroid hormone in the heart. At the molecular level, these disturbances have been shown to result from both genomic and nongenomic effects of thyroid hormone in the cardiovascular system (6). Thyroid hormone regulates the expression of structural proteins, like α- and β-myosin heavy chains in cardiac myocytes, and of key regulatory proteins through binding of T3 to nuclear receptors that activate or repress transcription of several specific genes. Intracellular calcium cycling via sarcoplasmic reticulum calcium-activated ATPase and its inhibitor, phospholamban, which are regulated by thyroid hormone in opposite ways, is thought to be largely responsible for enhanced contractile function and diastolic relaxation (22). These mechanisms underlie the reduced velocity of shortening and rate of tension development observed in papillary muscle from hypothyroid animals (23). Hypothyroidism, at any end-diastolic volume, blunts the development of myocardial force in early systole, which lengthens the time required for the intraventricular pressure to reach the arterial diastolic pressure and initiate the ejective phase.

Impaired development of myocardial force plays a major role in the abnormalities found in ICT and ICT/ET ratio, both in primary and central hypothyroidism, which improved after T4 replacement in correlation with changes in serum thyroid hormone levels. In addition, left ventricle ejection fraction, a much less sensitive marker of tissue hypothyroidism, was significantly decreased in overt hypothyroidism and also improved after treatment. Although diastolic function, as reflected by the isovolumic relaxation time, was significantly impaired only in overt primary hypothyroidism, it was improved by T4 replacement in both overt and subclinical primary hypothyroidism. MPI, an index that combines both systolic (ICT and ET) and diastolic (isovolumic relaxation time) time intervals, was also increased in hypothyroidism and improved in correlation with changes in serum thyroid hormones.

Although other pituitary hormone deficiencies like GH, glucocorticoid, and sex steroids were highly prevalent in our patients with hypothalamic–pituitary disease, they are unlikely to have had a major influence in the echocardiographic diagnosis of subclinical central hypothyroidism. First, these deficiencies, either treated or untreated, were equally distributed between patients with and without echocardiographically defined hypothyroidism. Second, similar abnormalities were also found in subclinical primary hypothyroidism with similar serum FT4 levels, which also improved after T4 replacement. Third, these echocardiographic abnormalities in patients with hypothalamic–pituitary disease and low serum FT4 were not more severe than in overt primary hypothyroidism.

A role for GH in heart morphology and function has been supported by clinical and experimental evidence (24, 25, 26, 27). Echocardiographic assessment of patients with GH deficiency has shown reduced cardiac mass, especially in childhood-onset deficiency, but the functional abnormalities have been reportedly subtle and best shown by radionuclide angiography (27). A meta-analysis of the echocardiographic effects of GH replacement in adults has shown improvement in left ventricle mass and stroke volume, but not in fractional shortening (28). However, none of these reports assessed the echocardiographic parameters selected in our study. Notwithstanding, the interaction between GH and thyroid hormones has relevant diagnostic and therapeutic implications in patients with hypothalamic–pituitary disease (29). Accordingly, GH replacement has been shown to decrease serum FT4 and reverse T3 and to increase serum T3 by improving peripheral T4 to T3 conversion (30). In practice, the T4-lowering effect of GH has been shown to unmask biochemical hypothyroidism in 36–47% of patients with hypothalamic–pituitary disease (31, 32). On the other hand, since untreated GH deficiency is a state of decreased T3 generation and GH improves T4 biological effects, thyroid status can be influenced by GH replacement or withdrawal. In fact, we have shown that biologically appropriate target levels of serum FT4 during l-T4 replacement should be higher in untreated GH deficiency (33).

The main limitation to the use of echocardiographic parameters in the diagnosis of hypothyroidism is the coexistence of cardiac disease. Accordingly, patients with positive clinical history of cardiac disease, hypertension, acromegaly, and Cushing's disease were not included and those with structural echocardiographic abnormalities were excluded by our study protocol. Nevertheless, further studies are necessary to elucidate whether these exclusion criteria could be less stringent in order to include hypertensive, acromegalic, and Cushing's disease patients with controlled hypertension who do not show any structural abnormalities in the echocardiographic evaluation. Another potential limitation is the use of drugs that could influence the diagnostic echocardiographic parameters via changes in circulating volume and/or peripheral vascular resistance, such as diuretics and some antihypertensive drugs, although their effects are reportedly small (34). Another potential, albeit limited influence is the age-related physiological impairment of myocardial relaxation that may increase MPI, but not ICT, especially after the sixth decade (35).

Patients with hypopituitarism have increased all-cause mortality with cardiovascular disease as the leading etiology (36). Analysis of mortality in hypopituitary cohorts has been challenging due to diversity of underlying etiologies, treatment modalities, hormone deficiencies, and hormone replacements (37). Subclinical primary hypothyroidism, on the other hand, has been associated with increased risk of coronary heart disease events and mortality (38). In this context, our results indicate that echocardiography should have a major role in assessing thyroid status in patients with hypothalamic–pituitary disease and normal serum FT4 levels.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

The study was partially supported by the research grant of Centro de Estudos de Endocrinologia da Escola Paulista de Medicina (CENEPAM). The funding organization had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Acknowledgements

The authors are grateful for the support from Erika Barbosa Ribeiro on the patients' selection work.

References

  • 1

    Beck-PeccozPAmrSMenezes-FerreiraMMFagliaGWeintraubBD. Decreased receptor binding of biologically inactive thyrotropin in central hypothyroidism. Effect of treatment with thyrotropin-releasing hormone. New England Journal of Medicine198531210851090. doi:10.1056/NEJM198504253121703.

    • Search Google Scholar
    • Export Citation
  • 2

    OliveiraJHPersaniLBeck-PeccozPAbuchamJ. Investigating the paradox of hypothyroidism and increased serum thyrotropin (TSH) levels in Sheehan's syndrome: characterization of TSH carbohydrate content and bioactivity. Journal of Clinical Endocrinology and Metabolism20018616941699. doi:10.1210/jc.86.4.1694.

    • Search Google Scholar
    • Export Citation
  • 3

    ShimonICohenOLubetskyAOlchovskyD. Thyrotropin suppression by thyroid hormone replacement is correlated with thyroxine level normalization in central hypothyroidism. Thyroid200212823827. doi:10.1089/105072502760339406.

    • Search Google Scholar
    • Export Citation
  • 4

    FerrettiEPersaniLJaffrain-ReaMLGiambonaSTamburranoGBeck-PeccozP. Evaluation of the adequacy of levothyroxine replacement therapy in patients with central hypothyroidism. Journal of Clinical Endocrinology and Metabolism199984924929. doi:10.1210/jc.84.3.924.

    • Search Google Scholar
    • Export Citation
  • 5

    Hartoft-NielsenMLLangeMRasmussenAKSchererSZimmermann-BelsingTFeldt-RasmussenU. Thyrotropin-releasing hormone stimulation test in patients with pituitary pathology. Hormone Research2004615357. doi:10.1159/000075239.

    • Search Google Scholar
    • Export Citation
  • 6

    KleinIOjamaaK. Thyroid hormone and the cardiovascular system. New England Journal of Medicine2001344501509. doi:10.1056/NEJM200105103441901.

    • Search Google Scholar
    • Export Citation
  • 7

    AmidiMLeonDFDeGrootWJKroetzFWLeonardJJ. Effect of the thyroid state on myocardial contractility and ventricular ejection rate in man. Circulation196838229239. doi:10.1161/01.CIR.38.2.229.

    • Search Google Scholar
    • Export Citation
  • 8

    TaylorRRCovellJWRossJJr. Influence of the thyroid state on left ventricular tension-velocity relations in the intact, sedated dog. Journal of Clinical Investigation196948775784. doi:10.1172/JCI106035.

    • Search Google Scholar
    • Export Citation
  • 9

    HillisWSBremnerWFLawrieTDThomsonJA. Systolic time intervals in thyroid disease. Clinical Endocrinology19754617624. doi:10.1111/j.1365-2265.1975.tb01931.x.

    • Search Google Scholar
    • Export Citation
  • 10

    CrowleyWFJrRidgwayECBoughEWFrancisGSDanielsGHKouridesIAMyersGSMaloofF. Noninvasive evaluation of cardiac function in hypothyroidism. Response to gradual thyroxine replacement. New England Journal of Medicine197729616. doi:10.1056/NEJM197701062960101.

    • Search Google Scholar
    • Export Citation
  • 11

    WeisslerAMHarrisWSSchoenfeldCD. Bedside technics for the evaluation of ventricular function in man. American Journal of Cardiology196923577583. doi:10.1016/0002-9149(69)90012-5.

    • Search Google Scholar
    • Export Citation
  • 12

    LangRMBierigMDevereuxRBFlachskampfFAFosterEPellikkaPAPicardMHRomanMJSewardJShanewiseJSSolomonSDSpencerKTSuttonMSStewartWJ. Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. Journal of the American Society of Echocardiography20051814401463. doi:10.1016/j.echo.2005.10.005.

    • Search Google Scholar
    • Export Citation
  • 13

    KahalyGMohr-KahalySBeyerJMeyerJ. Left ventricular function analyzed by Doppler and echocardiographic methods in short-term hypothyroidism. American Journal of Cardiology199575645648. doi:10.1016/S0002-9149(99)80641-9.

    • Search Google Scholar
    • Export Citation
  • 14

    MonzaniFDi BelloVCaraccioNBertiniAGiorgiDGiustiCFerranniniE. Effect of levothyroxine on cardiac function and structure in subclinical hypothyroidism: a double blind, placebo-controlled study. Journal of Clinical Endocrinology and Metabolism20018611101115. doi:10.1210/jc.86.3.1110.

    • Search Google Scholar
    • Export Citation
  • 15

    VitaleGGalderisiMLupoliGACelentanoAPietropaoloIParentiNDe DivitiisOLupoliG. Left ventricular myocardial impairment in subclinical hypothyroidism assessed by a new ultrasound tool: pulsed tissue Doppler. Journal of Clinical Endocrinology and Metabolism20028743504355. doi:10.1210/jc.2002-011764.

    • Search Google Scholar
    • Export Citation
  • 16

    BiondiBPalmieriEALombardiGFazioS. Subclinical hypothyroidism and cardiac function. Thyroid200212505510. doi:10.1089/105072502760143890.

    • Search Google Scholar
    • Export Citation
  • 17

    YaziciMGorguluSSertbasYErbilenEAlbayrakSYildizOUyanC. Effects of thyroxin therapy on cardiac function in patients with subclinical hypothyroidism: index of myocardial performance in the evaluation of left ventricular function. International Journal of Cardiology200495135143. doi:10.1016/j.ijcard.2003.05.015.

    • Search Google Scholar
    • Export Citation
  • 18

    TeichholzLEKreulenTHermanMVGorlinR. Problems in echocardiographic volume determinations: echocardiographic–angiographic correlations in the presence of absence of asynergy. American Journal of Cardiology197637711. doi:10.1016/0002-9149(76)90491-4.

    • Search Google Scholar
    • Export Citation
  • 19

    TeiCLingLHHodgeDOBaileyKROhJKRodehefferRJTajikAJSewardJB. New index of combined systolic and diastolic myocardial performance: a simple and reproducible measure of cardiac function – a study in normals and dilated cardiomyopathy. Journal of Cardiology199526357366.

    • Search Google Scholar
    • Export Citation
  • 20

    DoinFLBorges MdaRCamposOde Camargo CarvalhoACde PaolaAAPaivaMGAbuchamJMoisesVA. Effect of central hypothyroidism on Doppler-derived myocardial performance index. Journal of the American Society of Echocardiography200417622629. doi:10.1016/j.echo.2004.03.010.

    • Search Google Scholar
    • Export Citation
  • 21

    LavineSJ. Effect of heart rate and preload on index of myocardial performance in the normal and abnormal left ventricle. Journal of the American Society of Echocardiography200518133141. doi:10.1016/j.echo.2004.08.036.

    • Search Google Scholar
    • Export Citation
  • 22

    KleinIDanziS. Thyroid disease and the heart. Circulation200711617251735. doi:10.1161/CIRCULATIONAHA.106.678326.

  • 23

    BuccinoRASpannJFJrPoolPESonnenblickEHBraunwaldE. Influence of the thyroid state on the intrinsic contractile properties and energy stores of the myocardium. Journal of Clinical Investigation19674616691682. doi:10.1172/JCI105658.

    • Search Google Scholar
    • Export Citation
  • 24

    TimsitJRiouBBertheratJWisnewskyCKatoNSWeisbergASLubetzkiJLecarpentierYWinegradSMercadierJJ. Effects of chronic growth hormone hypersecretion on intrinsic contractility, energetics, isomyosin pattern, and myosin adenosine triphosphatase activity of rat left ventricle. Journal of Clinical Investigation199086507515. doi:10.1172/JCI114737.

    • Search Google Scholar
    • Export Citation
  • 25

    ItoHHiroeMHirataYTsujinoMAdachiSShichiriMKoikeANogamiAMarumoF. Insulin-like growth factor-I induces hypertrophy with enhanced expression of muscle specific genes in cultured rat cardiomyocytes. Circulation19938717151721. doi:10.1161/01.CIR.87.5.1715.

    • Search Google Scholar
    • Export Citation
  • 26

    DelafontaineP. Insulin-like growth factor I and its binding proteins in the cardiovascular system. Cardiovascular Research199530825834. doi:10.1016/S0008-6363(95)00163-8.

    • Search Google Scholar
    • Export Citation
  • 27

    ColaoA. The GH–IGF-I axis and the cardiovascular system: clinical implications. Clinical Endocrinology200869347358. doi:10.1111/j.1365-2265.2008.03292.x.

    • Search Google Scholar
    • Export Citation
  • 28

    MaisonPChansonP. Cardiac effects of growth hormone in adults with growth hormone deficiency: a meta-analysis. Circulation200310826482652. doi:10.1161/01.CIR.0000100720.01867.1D.

    • Search Google Scholar
    • Export Citation
  • 29

    BehanLAMonsonJPAghaA. The interaction between growth hormone and the thyroid axis in hypopituitary patients. Clinical Endocrinology201174281288. doi:10.1111/j.1365-2265.2010.03815.x.

    • Search Google Scholar
    • Export Citation
  • 30

    PortesESOliveiraJHMacCagnanPAbuchamJ. Changes in serum thyroid hormones levels and their mechanisms during long-term growth hormone (GH) replacement therapy in GH deficient children. Clinical Endocrinology200053183189. doi:10.1046/j.1365-2265.2000.01071.x.

    • Search Google Scholar
    • Export Citation
  • 31

    PorrettiSGiavoliCRonchiCLombardiGZaccariaMValleDArosioMBeck-PeccozP. Recombinant human GH replacement therapy and thyroid function in a large group of adult GH-deficient patients: when does l-T(4) therapy become mandatory?Journal of Clinical Endocrinology and Metabolism20028720422045. doi:10.1210/jc.87.5.2042.

    • Search Google Scholar
    • Export Citation
  • 32

    AghaAWalkerDPerryLDrakeWMChewSLJenkinsPJGrossmanABMonsonJP. Unmasking of central hypothyroidism following growth hormone replacement in adult hypopituitary patients. Clinical Endocrinology2007667277.

    • Search Google Scholar
    • Export Citation
  • 33

    MartinsMRDoinFCKomatsuWRBarros-NetoTLMoisesVAAbuchamJ. Growth hormone replacement improves thyroxine biological effects: implications for management of central hypothyroidism. Journal of Clinical Endocrinology and Metabolism20079241444153. doi:10.1210/jc.2007-0941.

    • Search Google Scholar
    • Export Citation
  • 34

    MollerJEPoulsenSHEgstrupK. Effect of preload alternations on a new Doppler echocardiographic index of combined systolic and diastolic performance. Journal of the American Society of Echocardiography19991210651072. doi:10.1016/S0894-7317(99)70103-3.

    • Search Google Scholar
    • Export Citation
  • 35

    SpencerKTKirkpatrickJNMor-AviVDecaraJMLangRM. Age dependency of the Tei index of myocardial performance. Journal of the American Society of Echocardiography200417350352. doi:10.1016/j.echo.2004.01.003.

    • Search Google Scholar
    • Export Citation
  • 36

    RosenTBengtssonBA. Premature mortality due to cardiovascular disease in hypopituitarism. Lancet1990336285288. doi:10.1016/0140-6736(90)91812-O.

    • Search Google Scholar
    • Export Citation
  • 37

    SherlockMAyukJTomlinsonJWToogoodAAAragon-AlonsoASheppardMCBatesASStewartPM. Mortality in patients with pituitary disease. Endocrine Reviews201031301342. doi:10.1210/er.2009-0033.

    • Search Google Scholar
    • Export Citation
  • 38

    RodondiNden ElzenWPBauerDCCappolaARRazviSWalshJPAsvoldBOIervasiGImaizumiMColletTHBremnerAMaisonneuvePSgarbiJAKhawKTVanderpumpMPNewmanABCornuzJFranklynJAWestendorpRGVittinghoffEGusseklooJ. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. Journal of the American Medical Association201030413651374. doi:10.1001/jama.2010.1361.

    • Search Google Scholar
    • Export Citation

If the inline PDF is not rendering correctly, you can download the PDF file here.

 

     European Society of Endocrinology

Related Articles

Article Information

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 747 615 9
PDF Downloads 609 548 16

Altmetrics

Figures

  • View in gallery

    ROC curves and the corresponding AUC for (A) the isovolumic contraction time (ICT), (B) the ratio between ICT and ejection time, and (C) the myocardial performance index (MPI) as markers of hypothyroidism in patients with overt primary and central hypothyroidism. An AUC value of 0.5 is no better than expected by chance and a value of 1.0 indicates a perfect diagnostic marker. Arrows indicate the chosen diagnostic cut-off values.

  • View in gallery

    Selected diagnostic echocardiographic parameters in patients with overt and subclinical primary hypothyroidism, overt central hypothyroidism, hypothalamic–pituitary disease with normal serum free thyroxine (FT4), and controls. Each circle represents one patient. Dashed horizontal lines indicate the chosen cut-off values: 53 ms for the ICT, 0.18 for the ratio between ICT and ET, and 0.46 for the MPI. Patients with hypothalamic–pituitary disease and normal FT4 that had at least one of the three parameters above the cut-off value were diagnosed as subclinical central hypothyroidism and are represented by solid circles.

  • View in gallery

    Diagnostic parameters before and after thyroxine (T4) intervention in patients with overt primary, overt central, subclinical primary, and subclinical central hypothyroidism. Box and whisker plots show the 10th, 25th, 50th (median), 75th, and 90th percentile values for the isovolumic contraction time (ICT), the ratio between ICT and ejection time (ET), and the myocardial performance index, before (gray boxes) and after (white boxes) T4 intervention in patients with primary and central overt and subclinical hypothyroidism. *P<0.05, paired t-test. Black dots represent outliers. Values in parentheses are the numbers of patients in each group.

  • View in gallery

    Correlations between changes (Δ=posttreatment minus pretreatment values) in serum FT4 and each echocardiographic diagnostic parameter after levothyroxine in patients with primary (solid circles) and central (open circles) overt and subclinical hypothyroidism (n=42). Slanting lines represent linear regression lines between parameters. FT4, free thyroxine; ICT, isovolumic contraction time; ICT/ET, ICT/ejection time ratio; MPI, myocardial performance index.

References

  • 1

    Beck-PeccozPAmrSMenezes-FerreiraMMFagliaGWeintraubBD. Decreased receptor binding of biologically inactive thyrotropin in central hypothyroidism. Effect of treatment with thyrotropin-releasing hormone. New England Journal of Medicine198531210851090. doi:10.1056/NEJM198504253121703.

    • Search Google Scholar
    • Export Citation
  • 2

    OliveiraJHPersaniLBeck-PeccozPAbuchamJ. Investigating the paradox of hypothyroidism and increased serum thyrotropin (TSH) levels in Sheehan's syndrome: characterization of TSH carbohydrate content and bioactivity. Journal of Clinical Endocrinology and Metabolism20018616941699. doi:10.1210/jc.86.4.1694.

    • Search Google Scholar
    • Export Citation
  • 3

    ShimonICohenOLubetskyAOlchovskyD. Thyrotropin suppression by thyroid hormone replacement is correlated with thyroxine level normalization in central hypothyroidism. Thyroid200212823827. doi:10.1089/105072502760339406.

    • Search Google Scholar
    • Export Citation
  • 4

    FerrettiEPersaniLJaffrain-ReaMLGiambonaSTamburranoGBeck-PeccozP. Evaluation of the adequacy of levothyroxine replacement therapy in patients with central hypothyroidism. Journal of Clinical Endocrinology and Metabolism199984924929. doi:10.1210/jc.84.3.924.

    • Search Google Scholar
    • Export Citation
  • 5

    Hartoft-NielsenMLLangeMRasmussenAKSchererSZimmermann-BelsingTFeldt-RasmussenU. Thyrotropin-releasing hormone stimulation test in patients with pituitary pathology. Hormone Research2004615357. doi:10.1159/000075239.

    • Search Google Scholar
    • Export Citation
  • 6

    KleinIOjamaaK. Thyroid hormone and the cardiovascular system. New England Journal of Medicine2001344501509. doi:10.1056/NEJM200105103441901.

    • Search Google Scholar
    • Export Citation
  • 7

    AmidiMLeonDFDeGrootWJKroetzFWLeonardJJ. Effect of the thyroid state on myocardial contractility and ventricular ejection rate in man. Circulation196838229239. doi:10.1161/01.CIR.38.2.229.

    • Search Google Scholar
    • Export Citation
  • 8

    TaylorRRCovellJWRossJJr. Influence of the thyroid state on left ventricular tension-velocity relations in the intact, sedated dog. Journal of Clinical Investigation196948775784. doi:10.1172/JCI106035.

    • Search Google Scholar
    • Export Citation
  • 9

    HillisWSBremnerWFLawrieTDThomsonJA. Systolic time intervals in thyroid disease. Clinical Endocrinology19754617624. doi:10.1111/j.1365-2265.1975.tb01931.x.

    • Search Google Scholar
    • Export Citation
  • 10

    CrowleyWFJrRidgwayECBoughEWFrancisGSDanielsGHKouridesIAMyersGSMaloofF. Noninvasive evaluation of cardiac function in hypothyroidism. Response to gradual thyroxine replacement. New England Journal of Medicine197729616. doi:10.1056/NEJM197701062960101.

    • Search Google Scholar
    • Export Citation
  • 11

    WeisslerAMHarrisWSSchoenfeldCD. Bedside technics for the evaluation of ventricular function in man. American Journal of Cardiology196923577583. doi:10.1016/0002-9149(69)90012-5.

    • Search Google Scholar
    • Export Citation
  • 12

    LangRMBierigMDevereuxRBFlachskampfFAFosterEPellikkaPAPicardMHRomanMJSewardJShanewiseJSSolomonSDSpencerKTSuttonMSStewartWJ. Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. Journal of the American Society of Echocardiography20051814401463. doi:10.1016/j.echo.2005.10.005.

    • Search Google Scholar
    • Export Citation
  • 13

    KahalyGMohr-KahalySBeyerJMeyerJ. Left ventricular function analyzed by Doppler and echocardiographic methods in short-term hypothyroidism. American Journal of Cardiology199575645648. doi:10.1016/S0002-9149(99)80641-9.

    • Search Google Scholar
    • Export Citation
  • 14

    MonzaniFDi BelloVCaraccioNBertiniAGiorgiDGiustiCFerranniniE. Effect of levothyroxine on cardiac function and structure in subclinical hypothyroidism: a double blind, placebo-controlled study. Journal of Clinical Endocrinology and Metabolism20018611101115. doi:10.1210/jc.86.3.1110.

    • Search Google Scholar
    • Export Citation
  • 15

    VitaleGGalderisiMLupoliGACelentanoAPietropaoloIParentiNDe DivitiisOLupoliG. Left ventricular myocardial impairment in subclinical hypothyroidism assessed by a new ultrasound tool: pulsed tissue Doppler. Journal of Clinical Endocrinology and Metabolism20028743504355. doi:10.1210/jc.2002-011764.

    • Search Google Scholar
    • Export Citation
  • 16

    BiondiBPalmieriEALombardiGFazioS. Subclinical hypothyroidism and cardiac function. Thyroid200212505510. doi:10.1089/105072502760143890.

    • Search Google Scholar
    • Export Citation
  • 17

    YaziciMGorguluSSertbasYErbilenEAlbayrakSYildizOUyanC. Effects of thyroxin therapy on cardiac function in patients with subclinical hypothyroidism: index of myocardial performance in the evaluation of left ventricular function. International Journal of Cardiology200495135143. doi:10.1016/j.ijcard.2003.05.015.

    • Search Google Scholar
    • Export Citation
  • 18

    TeichholzLEKreulenTHermanMVGorlinR. Problems in echocardiographic volume determinations: echocardiographic–angiographic correlations in the presence of absence of asynergy. American Journal of Cardiology197637711. doi:10.1016/0002-9149(76)90491-4.

    • Search Google Scholar
    • Export Citation
  • 19

    TeiCLingLHHodgeDOBaileyKROhJKRodehefferRJTajikAJSewardJB. New index of combined systolic and diastolic myocardial performance: a simple and reproducible measure of cardiac function – a study in normals and dilated cardiomyopathy. Journal of Cardiology199526357366.

    • Search Google Scholar
    • Export Citation
  • 20

    DoinFLBorges MdaRCamposOde Camargo CarvalhoACde PaolaAAPaivaMGAbuchamJMoisesVA. Effect of central hypothyroidism on Doppler-derived myocardial performance index. Journal of the American Society of Echocardiography200417622629. doi:10.1016/j.echo.2004.03.010.

    • Search Google Scholar
    • Export Citation
  • 21

    LavineSJ. Effect of heart rate and preload on index of myocardial performance in the normal and abnormal left ventricle. Journal of the American Society of Echocardiography200518133141. doi:10.1016/j.echo.2004.08.036.

    • Search Google Scholar
    • Export Citation
  • 22

    KleinIDanziS. Thyroid disease and the heart. Circulation200711617251735. doi:10.1161/CIRCULATIONAHA.106.678326.

  • 23

    BuccinoRASpannJFJrPoolPESonnenblickEHBraunwaldE. Influence of the thyroid state on the intrinsic contractile properties and energy stores of the myocardium. Journal of Clinical Investigation19674616691682. doi:10.1172/JCI105658.

    • Search Google Scholar
    • Export Citation
  • 24

    TimsitJRiouBBertheratJWisnewskyCKatoNSWeisbergASLubetzkiJLecarpentierYWinegradSMercadierJJ. Effects of chronic growth hormone hypersecretion on intrinsic contractility, energetics, isomyosin pattern, and myosin adenosine triphosphatase activity of rat left ventricle. Journal of Clinical Investigation199086507515. doi:10.1172/JCI114737.

    • Search Google Scholar
    • Export Citation
  • 25

    ItoHHiroeMHirataYTsujinoMAdachiSShichiriMKoikeANogamiAMarumoF. Insulin-like growth factor-I induces hypertrophy with enhanced expression of muscle specific genes in cultured rat cardiomyocytes. Circulation19938717151721. doi:10.1161/01.CIR.87.5.1715.

    • Search Google Scholar
    • Export Citation
  • 26

    DelafontaineP. Insulin-like growth factor I and its binding proteins in the cardiovascular system. Cardiovascular Research199530825834. doi:10.1016/S0008-6363(95)00163-8.

    • Search Google Scholar
    • Export Citation
  • 27

    ColaoA. The GH–IGF-I axis and the cardiovascular system: clinical implications. Clinical Endocrinology200869347358. doi:10.1111/j.1365-2265.2008.03292.x.

    • Search Google Scholar
    • Export Citation
  • 28

    MaisonPChansonP. Cardiac effects of growth hormone in adults with growth hormone deficiency: a meta-analysis. Circulation200310826482652. doi:10.1161/01.CIR.0000100720.01867.1D.

    • Search Google Scholar
    • Export Citation
  • 29

    BehanLAMonsonJPAghaA. The interaction between growth hormone and the thyroid axis in hypopituitary patients. Clinical Endocrinology201174281288. doi:10.1111/j.1365-2265.2010.03815.x.

    • Search Google Scholar
    • Export Citation
  • 30

    PortesESOliveiraJHMacCagnanPAbuchamJ. Changes in serum thyroid hormones levels and their mechanisms during long-term growth hormone (GH) replacement therapy in GH deficient children. Clinical Endocrinology200053183189. doi:10.1046/j.1365-2265.2000.01071.x.

    • Search Google Scholar
    • Export Citation
  • 31

    PorrettiSGiavoliCRonchiCLombardiGZaccariaMValleDArosioMBeck-PeccozP. Recombinant human GH replacement therapy and thyroid function in a large group of adult GH-deficient patients: when does l-T(4) therapy become mandatory?Journal of Clinical Endocrinology and Metabolism20028720422045. doi:10.1210/jc.87.5.2042.

    • Search Google Scholar
    • Export Citation
  • 32

    AghaAWalkerDPerryLDrakeWMChewSLJenkinsPJGrossmanABMonsonJP. Unmasking of central hypothyroidism following growth hormone replacement in adult hypopituitary patients. Clinical Endocrinology2007667277.

    • Search Google Scholar
    • Export Citation
  • 33

    MartinsMRDoinFCKomatsuWRBarros-NetoTLMoisesVAAbuchamJ. Growth hormone replacement improves thyroxine biological effects: implications for management of central hypothyroidism. Journal of Clinical Endocrinology and Metabolism20079241444153. doi:10.1210/jc.2007-0941.

    • Search Google Scholar
    • Export Citation
  • 34

    MollerJEPoulsenSHEgstrupK. Effect of preload alternations on a new Doppler echocardiographic index of combined systolic and diastolic performance. Journal of the American Society of Echocardiography19991210651072. doi:10.1016/S0894-7317(99)70103-3.

    • Search Google Scholar
    • Export Citation
  • 35

    SpencerKTKirkpatrickJNMor-AviVDecaraJMLangRM. Age dependency of the Tei index of myocardial performance. Journal of the American Society of Echocardiography200417350352. doi:10.1016/j.echo.2004.01.003.

    • Search Google Scholar
    • Export Citation
  • 36

    RosenTBengtssonBA. Premature mortality due to cardiovascular disease in hypopituitarism. Lancet1990336285288. doi:10.1016/0140-6736(90)91812-O.

    • Search Google Scholar
    • Export Citation
  • 37

    SherlockMAyukJTomlinsonJWToogoodAAAragon-AlonsoASheppardMCBatesASStewartPM. Mortality in patients with pituitary disease. Endocrine Reviews201031301342. doi:10.1210/er.2009-0033.

    • Search Google Scholar
    • Export Citation
  • 38

    RodondiNden ElzenWPBauerDCCappolaARRazviSWalshJPAsvoldBOIervasiGImaizumiMColletTHBremnerAMaisonneuvePSgarbiJAKhawKTVanderpumpMPNewmanABCornuzJFranklynJAWestendorpRGVittinghoffEGusseklooJ. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. Journal of the American Medical Association201030413651374. doi:10.1001/jama.2010.1361.

    • Search Google Scholar
    • Export Citation

Cited By

PubMed

Google Scholar