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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-0003
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 11 6185-6191
Copyright © 2005 by The Endocrine Society

Spontaneous Diurnal Thyrotropin Secretion Is Enhanced in Proportion to Circulating Leptin in Obese Premenopausal Women

Petra Kok, Ferdinand Roelfsema, Marijke Frölich, A. Edo Meinders and Hanno Pijl

Departments of General Internal Medicine (P.K., A.E.M., H.P.), Endocrinology and Metabolic Diseases (F.R.), and Clinical Chemistry (M.F.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands

Address all correspondence and requests for reprints to: Dr. Hanno Pijl, Leiden University Medical Center, Department of Internal Medicine (C4-83), P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: h.pijl{at}lumc.nl.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Recent evidence implicates leptin as an important modulator of thyroid axis activity.

Objective: The objective of this study was to study spontaneous 24-h TSH secretion and 24-h circulating leptin concentrations in obese and lean women.

Design: This was a prospective parallel study (2004).

Setting: This study was conducted at the Clinical Research Center (Leiden University Medical Center, Leiden, The Netherlands).

Participants: Twelve healthy obese premenopausal women (body mass index, 33.2 ± 0.9 kg/m2) and 11 lean controls (body mass index, 21.4 ± 0.5 kg/m2) were studied in the follicular phase of their menstrual cycle.

Intervention(s): There were no interventions in this study.

Main Outcome Measure(s): Spontaneous 24-h TSH concentrations (10-min time intervals) and secretion were calculated using waveform-independent deconvolution technique (pulse). Twenty-four-hour circulating leptin concentrations (20-min time intervals) were measured.

Results: Mean TSH concentration (obese, 1.9 ± 0.2 vs. lean, 1.1 ± 0.1 mU/liter; P = 0.009) and secretion rate (obese, 43.4 ± 5.5 vs. lean, 26.1 ± 2.2 mU/liter distribution volume·24 h; P = 0.011) were substantially enhanced in obesity, whereas the fasting free T4 (fT4) concentrations were similar (fT4 in obese, 15.4 ± 1.5 vs. in lean, 16.4 ± 1.5 pmol/liter; P = 0.147). TSH secretion was positively related to 24-h leptin concentrations (r2 = 0.31; P = 0.007).

Conclusions: TSH release is enhanced in the face of normal plasma fT4 concentrations in obese premenopausal women, and hyperleptinemia may well be involved in this neuroendocrine alteration.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE HYPOTHALAMIC PITUITARY thyroid (HPT) hormonal ensemble orchestrates a variety of metabolic processes, including thermogenesis and energy expenditure, thereby affecting energy balance (1, 2, 3). Because obesity is a phenotypic expression of energy imbalance (4), it is conceivable that obese individuals have altered HPT axis activity.

Numerous studies have evaluated HPT axis status in obese humans, and the results were conflicting. The majority of these studies suggests that there is no substantial change in basal thyroid hormone concentrations (5), although a few papers document serum T3 elevation in obese subjects (6, 7, 8). The basal serum TSH concentration in a single plasma sample was similar in obese and nonobese subjects in some studies (9, 10, 11), whereas others documented higher basal TSH concentrations in obese humans (6, 12). Also, some papers report a larger rise of plasma TSH in response to TRH stimulation in obese subjects, whereas other studies revealed normal or reduced TSH responses (9, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19). Because serum TSH concentrations fluctuate during the day, and circulating thyroid hormone levels are relatively stable, proper appreciation of HPT axis activity requires measurement of TSH release over 24 h (20), whereas thyroid hormone determination in a single sample usually suffices. To our knowledge, spontaneous TSH concentration profiles over 24 h have not been measured in obese humans. Here, we report data delineating 24-h TSH secretion in obese premenopausal women.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Twelve healthy obese premenopausal women [body mass index (BMI) > 30 kg/m2] and 11 lean controls (BMI 18–25 kg/m2) of similar sex and age were enrolled in this study, after giving written acknowledgment of informed consent for participation. All participants were required to have a regular menstrual cycle and not use oral contraceptives. Subjects were studied in the follicular phase of their menstrual cycle. Chronic disease, depression (present or in history), smoking, recent transmeridional flights, night shift work, weight change (>3 kg in 3 months), and use of medication were exclusion criteria. All subjects had an unremarkable medical history, and no abnormalities were found during physical examination, standard laboratory hematology, and blood chemistry and urine tests.

Body fat distribution

Total amount and location of excess body fat mass were determined in the obese women only. Total body fat mass was expressed as a percentage of total body weight and was quantified using dual energy x-ray absorptiometry (Hologic QDR4500; Hologic, Waltham, MA) (21). Visceral and sc adipose tissue areas were assessed in the obese women by MRI as described before, using a multislice fast spin echo sequence (Gyroscan-T5 whole-body scanner 0.5 Tesla, Philips Medical Systems, Best, The Netherlands) (22). MRI images were independently analyzed by two observers.

Clinical protocol

The protocol was approved by the Medical Ethics Committee of the Leiden University Medical Center (Leiden, The Netherlands). Subjects were admitted to the Clinical Research Unit of the Department of General Internal Medicine in the early follicular stage of their menstrual cycle. A cannula for blood sampling was inserted into an antecubital vein. The cannula was attached to a three-way stopcock and kept patent by a continuous saline infusion. Blood samples were taken with S-monovette (Sarstedt, Etten-Leur, The Netherlands) at 10-min intervals for determination of plasma TSH concentrations and at 20-min intervals for the determination of leptin concentrations. Subjects remained recumbent, except for bathroom visits. No daytime naps were allowed. Meals were served according to a fixed time schedule. Lights were switched off at 2300 h. Vital signs were recorded at regular time intervals, and great care was taken not to disturb patients while sampling blood during their sleep (no electroencephalography sleep recording was performed).

Assays

Samples were centrifuged at 4000 rotations/min at 4 C for 20 min, within 60 min of sampling. Subsequently, plasma was divided into separate aliquots and frozen at –80 C until assays were performed. Samples of each subject were determined in the same assay run. Plasma TSH concentrations were measured with a time-resolved immunofluorometric assay (Wallac, Turku, Finland), and its standard was calibrated against the World Health Organization second standard International Reference Preparation (80/558) hTSH for immunoassays. The limit of detection was 0.05 mU/liter, and the interassay coefficient of variation was less then 5%. Plasma leptin concentrations were determined by RIA (Linco Research, St. Charles, MO) with a detection limit of 0.5 µg/liter, and the interassay coefficient ranged from 6–7%. Basal free T4 (fT4) was estimated using an automated system (Elecsys 2010, Roche Diagnostics Nederland BV, Almere, Netherlands) and by dialysis as described before (23). Basal serum glucose, glycosylated hemoglobin, apolipoprotein A-1, and triglyceride levels were measured using a fully automated system (P800, Integra 800, and Hitachi 747, respectively, Roche Diagnostics Nederland BV). Estradiol was determined by RIA (Diagnostic Systems Laboratory, Webster, TX).

Calculations and statistics

The Cluster program describes various characteristics of pulsatile hormone concentration profiles (24). A concentration peak is defined as a significant increase in the test peak cluster vs. the test nadir cluster. We used a 2 x 1 cluster configuration (two samples in the test nadir and one in the test peak) and Student’s t statistics of 2.0 for significant up strokes and down strokes in TSH levels to constrain the false-positive rate of peak identification to less than 5% of signal-free noise. The locations and durations of all significant plasma hormone peaks were identified, and the following parameters were determined: mean TSH concentration, peak frequency, mean peak width, mean peak height (maximum concentration attained within the peak), mean peak area (above the baseline), overall mean concentration of the interpeak valley (nadir), and the total area under the curve.

Pulse

Deconvolution analysis estimates hormone secretion and clearance rates based on hormone concentration time-series. The pulse algorithm is a waveform-independent deconvolution method, which can be used for calculation of hormonal secretion, without specifying shape, number, and time of secretory events (25). The technique requires a priori specification of hormonal half-life in plasma. TSH disappearance from plasma is best described by a two-compartment model, characterized by a fast component half-life of 18 ± 3 min and a slow component half-life of 90 ± 5 min where the fractional contribution of the slow component to the overall decay amounts to 32% (data kindly provided by J. D. Veldhuis, Mayo Clinic, Rochester, MN). Pulse was used to quantify mean 24-h TSH secretion. Secretion rates were expressed per liter distribution volume.

Approximate entropy (ApEn)

ApEn is a scale- and model-independent statistic that assigns a nonnegative number to time series data, reflecting regularity of these data (26). Higher ApEn values denote greater relative randomness of hormone patterns. Normalized ApEn parameters of m = 1 (test range), r = 20% (threshold), and 1000 for the number of runs were used, as described previously (27). Hence, this member of the ApEn family is designated (1, 20%). The ApEn metric evaluates the consistency of recurrent subordinate (nonpulsatile) patterns in a time series and thus yields information distinct from and complementary deconvolution (pulse) analyses (28). Data are presented as normalized ApEn ratios, defined by the mean ratio of absolute ApEn to that of 1000 randomly shuffled versions of the same series. ApEn ratios close to 1.0 express high irregularity (maximum randomness) of pulsatile hormone patterns.

Diurnal rhythmicity

Nyctohemeral characteristics of TSH concentration patterns were determined using a robust curve fitting algorithm described by Cleveland [LOWESS analysis, SYSTAT version 11, Systat Inc, Richmond, CA (29, 30)]. The acrophase (clock time during 24 h at which TSH concentration is maximal) was the maximal value of the fitted curve. The amplitude of the rhythm was defined as half the difference of the nocturnal zenith and the daytime nadir. The relative amplitude was the maximal percentage increase of the nadir value.

Statistics

Data are presented as mean ± SEM, unless otherwise specified. Means of TSH concentration and secretion parameters of both groups were compared using two-tailed independent Student’s t test. Significance level was set at 0.05. Regression analysis was used to determine the correlation of BMI and mean 24-h leptin concentrations vs. mean 24-h TSH secretion in the obese and normal-weight premenopausal women together. Step-wise multiple regression analysis, with percentage total body fat and sc and visceral fat areas as independent variables, was used to determine correlations between specific measures of body fat distribution and diurnal TSH secretion rates in the obese subjects only.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Subject characteristics

Obese subjects had normal fasting glucose (mean, 5.3 ± 0.4; range, 4.8–6.0 mmol/liter; reference range lab, 3.5–5.5 mmol/liter), glycosylated hemoglobin (mean, 4.7 ± 0.3; range, 4.2–5.3%; reference range lab, 4.3–6.3%), triglyceride (mean, 1.4 ± 0.7; range, 0.7–2.9 mmol/liter; reference range lab, 0.80–1.94 mmol/liter), cholesterol (mean, 5.09 ± 0.81; range, 3.94–6.17 mmol/liter; reference range lab, 3.9–7.3 mmol/liter), and apolipoprotein A-1 (mean, 1.3 ± 0.1; range, 1.0–1.7 g/liter; reference range lab, 1.01–1.98 g/liter) levels. All subjects were clinically euthyroid, and fasting fT4 concentrations as well as fT4fraction (fraction of total T4) were measured by dialysis were similar in obese and lean subjects (fT4 obese, 15.4 ± 1.5 vs. lean, 16.4 ± 1.5 pmol/liter; P = 0.147 obese vs. lean; reference range lab, 10–24 pmol/liter; and fT4fraction, obese, 0.020 ± 0.001 vs. lean 0.022 ± 0.001, fraction of total T4; P = 0.08 obese vs. lean). Relevant subject characteristics are presented in Table 1Go.


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  		TABLE 1. Subject characteristics of lean and obese premenopausal women

 
Plasma hormone concentration profiles and TSH secretion

Various characteristics of 24-h TSH hormone concentration profiles were determined using the Cluster program. Mean 24-h TSH concentration, mean peak height (maximum concentration attained within the peak), overall mean concentration of the interpeak valley (nadir), and total area under the concentration curve were significantly higher, whereas peak frequency and peak width were unaltered in obese subjects compared with lean controls (Table 2Go and Fig. 1Go). A graphical illustration of representative TSH concentration profiles of two obese and two lean woman of identical age is presented in Fig. 2Go.


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  		TABLE 2. TSH concentration and secretion parameters in lean and obese premenopausal women

 


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  		FIG. 1. Mean serum TSH concentration time series of the obese (-•-) and control (-{circ}-) subjects. Data reflect sampling of blood every 10 min for 24 h. Blood sampling started at 1800 h. Lights were switched off, and subjects went to sleep at 2300 h until 0730 h the next morning (gray horizontal bar). Sleep was not interrupted. Vertical arrows indicate the time point at which the acrophase occurred (obese, 0100 h ± 1 h 26 min vs. lean, 0009 h ± 50 min, respectively; P = 0.033).

 


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  		FIG. 2. Representative 24-h TSH concentration profiles of two lean (-•-) and two obese women (-{circ}-). Data reflect sampling of blood every 10 min for 24 h. Blood sampling started at 1800 h. Lights were switched off, and subjects went to sleep at 2300 h until 0730 h the next morning (gray horizontal bar). Sleep was not interrupted. A, Lean woman, age 39 yr, BMI 21.0 kg/m2; and obese woman, age 39 yr, BMI 31.9 kg/m2. B, Lean woman, age 31 yr, BMI 24.8 kg/m2; and obese woman, age 31 yr, BMI 39.4 kg/m2.

 
Deconvolution analysis revealed that daily TSH secretion was significantly enhanced in the obese women compared with the lean controls (obese, 43.4 ± 5.5 vs. lean, 26.1 ± 2.2 mU/distribution volume·24 h; P = 0.011).

Diurnal variation 24-h TSH concentration profiles

The acrophase of the nyctohemeral TSH rhythm occurred at night at different clock times in obese and lean subjects (obese, 0100 h ± 1 h 26 min and lean, 0009 h ± 50 min, respectively; P = 0.033). The amplitude of the rhythm was not significantly increased in obese subjects (0.69 ± 0.11 mU/liter vs. lean, 0.51 ± 0.07 mU/liter, respectively; P = 0.206), whereas the relative increase in TSH concentration was significantly lower in the obese women (53.2 ± 5.0% vs. lean 79.5 ± 5.4%, respectively; P = 0.019).

Regularity of plasma TSH concentration-time series

ApEn ratios as well as ApEn values, which reflect regularity of plasma TSH concentration time series, were similar in the obese and normal-weight premenopausal women (ApEn ratios in obese, 0.56 ± 0.03 vs. in lean, 0.52 ± 0.04, respectively; P = 0.451; and ApEn values in obese, 1.00 ± 0.06 vs. in lean, 0.92 ± 0.08, respectively; P = 0.390).

Body composition and TSH secretion

Both obese and lean subjects (n = 23) were included in the regression analysis of BMI (range 18.3–39.4 kg/m2) vs. daily TSH secretion. BMI was positively related to mean diurnal TSH release (r2 = 0.29; P = 0.010). Correlations between specific measures of body fat distribution and diurnal TSH secretion rates were determined in the obese subjects only. The obese subjects had a mean percentage body fat of 40.7 ± 1.0% (36.9–46.3%). Mean sizes of their visceral and sc fat areas were 392 ± 27 (274–539) cm2 and 1326 ± 57 (1106–1709) cm2, respectively. Multiple regression analysis, with percentage total body fat and visceral and sc fat areas as independent variables, revealed that there was no significant correlation between any of these specific body composition parameters and daily TSH secretion (percent total body fat vs. 24-h TSH secretion, r2 = 0.12; P = 0.352; sc fat area vs. diurnal TSH release, r2 = 0.02; P = 0.692; and abdominal fat area vs. 24-h TSH secretion, r2 = 0.15; P = 0.306).

Leptin and 24-h TSH secretion

Both obese and lean subjects (n = 23) were included in regression analysis of mean 24-h leptin concentrations (range, 4.9–50.3 µg/liter) vs. 24-h TSH production. Regression analysis revealed that mean 24-h leptin concentrations were significantly positively related to mean diurnal TSH release (r2 = 0.31, ß = 0.577; P = 0.007; Fig. 3Go). When both leptin and BMI were entered as independent variables into the model simultaneously, none of these parameters did significantly correlate with mean diurnal TSH release. Estrogen was not related to diurnal TSH secretion and did not influence the correlation between leptin and TSH, if added as independent variable to the model.



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  		FIG. 3. Correlation between leptin and 24-h TSH secretion. Both obese and lean women (n = 22) were included in correlation analysis of 24-h mean leptin concentrations (range, 4.9–50.3 µg/liter) vs. daily TSH secretion.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study demonstrates that spontaneous pulsatile TSH release over 24 h is substantially enhanced in obese premenopausal women compared with lean controls of similar age and sex. The higher diurnal TSH secretion rate appears to be primarily attributable to an increase of TSH pulse amplitude, whereas the number of pulses is similar. The mean 24-h TSH secretion rate was positively related to circulating leptin concentrations.

As far as we are aware, this is the first study to directly compare spontaneous circadian TSH secretion in lean and obese humans. Previous investigators have primarily evaluated plasma hormone concentrations in a single blood sample or in response to TRH administration as a measure of HPT axis status in obese individuals (5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 31). In this context, some authors report similar TSH concentrations in obese and normal-weight humans (10, 11), but others have shown that TSH concentrations are significantly elevated in proportion to BMI in obese women (6), which is in line with the findings of the present study. It seems important to emphasize that we studied women of reproductive age in the early follicular phase of their menstrual cycle and that our data should therefore be judged within the framework of this physiological context. Indeed, it remains to be established whether obese women in other stages of their cycle or obese men have similar elevations of circulating TSH. Also, one has to take into account that the waveform-dependent deconvolution technique we used requires a priori definition of TSH clearance. Therefore, we cannot rule out the possibility that changes in plasma TSH clearance contribute to the elevated circulating TSH levels in obese women compared with normal controls.

TSH synthesis and secretion are primarily controlled by the stimulatory action of TRH and the negative feedback restraint by thyroid hormones (T4 and T3), whereas other factors, including leptin, dopamine, somatostatin, and serotonin act to modulate release (for review, see Ref.32). Several studies provide strong evidence that leptin stimulates TSH production in rodents and humans. Leptin counteracts the starvation-induced reduction of thyroid hormone and TSH release in rodents (33, 34) by preventing the decline of TRH mRNA expression in paraventricular nucleus neurons that occurs during fasting (35). Furthermore, clinical studies have shown that leptin replacement significantly blunts the fasting-induced fall in TSH secretion in healthy lean men and in normal-weight women of reproductive age in the early follicular phase of their menstrual cycle (36, 37). Moreover, circadian plasma leptin and TSH concentration rhythms exhibit significant pattern synchrony of ultradian fluctuations in humans (38). Finally, indirect evidence for a stimulatory impact of leptin on TSH secretion has also been found in various human disease states characterized by low circulating leptin levels. For example, plasma TSH levels are reduced in proportion to circulating leptin in narcoleptic patients (39). Moreover, both circulating leptin and TSH concentrations appear to be low in patients with anorexia nervosa, whereas weight gain is accompanied by a significant increase of both hormones in these patients (40, 41, 42, 43). The finding that 24-h TSH secretion was positively related to mean 24-h leptin concentrations in the present study is in line with the results of these studies. Although this simple correlation between leptin and TSH does not imply causality in a cross-sectional study, this finding may be interpreted as circumstantial evidence of a stimulatory impact of hyperleptinemia on TSH release in obese individuals.

Additionally, reduced dopamine D2 receptor (D2R)-mediated transmission in the brain may enhance TSH release in obese humans. Availability of D2R binding sites is considerably reduced in the brain of obese rodent models (44) and in striatal nuclei of obese humans (45). Moreover, we previously showed that spontaneous diurnal prolactin release is enhanced in obese premenopausal women, which supports the concept of diminished D2R signaling in human obesity because D2R activation is required for maintenance of low circulating prolactin levels (46). Dopamine exerts its inhibitory influence on TSH synthesis and release through D2R activation in thyrotrophs of the pituitary gland, and it appears to specifically reduce the amplitude of pulsatile TSH release, whereas it does not affect TSH pulse frequency (32). The present study shows that the increase of TSH secretion rates in obese subjects is primarily attributable to enhanced TSH pulse amplitude, whereas the number of pulses was similar to that in controls. These findings are in keeping with a putative role of reduced D2R dopaminergic tone in the anomalous TSH release profile in obese humans. Furthermore, although dopamine has an inhibitory effect on TSH secretion at the pituitary level, dopamine and dopamine agonists stimulate TRH release by the hypothalamus in rats (47), acting through the dopamine 2 receptor (48). TRH plays an important role in the posttranslational processing of the oligosaccharide moieties of TSH and hence exerts an important influence on the biologic activity of TSH that is secreted (49). Thus, we speculate that reduced D2R signaling in hypothalamic nuclei may hamper the biological activity of TSH through diminution of TRH production in obese humans, which could explain why TSH levels are elevated in the face of normal fT4 in our obese subjects. Because D2R activity was not addressed directly in this study, it clearly requires further investigation to establish whether dopaminergic mechanisms indeed underlie enhanced TSH release in obese humans.

Alternatively, evidence has been provided that serotonin inhibits TSH secretion (50), although the literature on serotonergic control of TSH secretion is ambiguous. It has been suggested that a defect in hypothalamic serotonergic neurotransmission is involved in altered pituitary hormone release in obesity (51), and the elevated TSH response to TRH in obese subjects is normalized by serotonergic stimulation (16). Thus, reduced serotonergic signaling might be among the physiological cues explaining the elevated TSH levels in the obese women.

Finally, somatostatin inhibits TSH secretion (32). Somatostatin is known as the major inhibitor of GH release. Both spontaneous and stimulated GH secretion is profoundly impaired in obesity, and a plethora of data implicates that obesity is associated with tonic somatostatin hypersecretion (52). Therefore, it seems not very likely that somatostatin is involved in the altered TSH secretion in obese women.

The fact that TSH plasma concentrations are elevated in obese humans in the face of normal fT4 levels has not been reported before. Although this phenomenon might be explained by impaired biological activity of TSH through reduced dopaminergic signaling (see above), it has also been shown that human obesity is frequently associated with unresponsiveness to exogenous TSH (53). In this context, it is noteworthy that the sensitivity of the thyroid gland to TSH is regulated by the autonomic nervous system (54). Specifically, sympathetic activity appears to inhibit the thyroid hormone response to TSH stimulation (55, 56). Thus, increased sympathetic activity associated with obesity (57, 58, 59) potentially contributes to the imbalance of the thyroid-pituitary axis observed here.

Finally, the acrophase of the TSH concentration patterns occurred significantly later during the night in the obese women than in the lean controls. The acrophase of TSH is believed to reflect the balance between the inhibitory effect of sleep and the increase of TSH release in the evening, regulated by neuronal signals emanating from the circadian master pacemaker, the suprachiasmatic nucleus (54). Thus, differential sleep patterns among obese and lean women may explain why the TSH phase shift occurs. Unfortunately, we did not perform electroencephalography sleep monitoring to substantiate this thesis. Although phase shifts of other neuroendocrine systems have been described in viscerally obese premenopausal women (60), both cause and consequence of the epiphasia (delayed timing) of the 24-h TSH hormonal release remain elusive.

In conclusion, we show here that daily TSH secretion is enhanced in obese premenopausal women, whereas fT4 concentrations are similar to those in lean controls. The 24-h TSH secretion was positively correlated with mean circulating leptin concentrations and BMI, which suggests that hyperleptinemia is involved in this alteration of HPT axis setting in obese premenopausal women.


   Acknowledgments
 
We gratefully thank Dr. H. Alec Ross (Department of Chemical Endocrinology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands) for the determination of fT4 levels by dialysis. This study could not have been performed without the efficient participation of the analysts of the clinical chemistry department (M. van Dijk-Besling and J. H. G. Haasnoot-van der Bent) and the clinical research assistants (E. J. M. Ladan- Eijgenraam and I. A. Sierat-van der Steen).


   Footnotes
 
First Published Online August 9, 2005

Abbreviations: ApEn, Approximate entropy; BMI, body mass index; D2R, D2 receptor; fT4, free T4; HPT, hypothalamic pituitary thyroid.

Received January 4, 2005.

Accepted August 2, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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