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High Circulating Thyrotropin Levels in Obese Women Are Reduced after Body Weight Loss Induced by Caloric Restriction

Departments of General Internal Medicine (P.K., J.G.L., A.E.M.), Endocrinology and Metabolic Diseases (F.R., H.P.), and Clinical Chemistry (M.F.), and Center for Human Drug Research (J.B.), 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: Previous clinical studies concerning the impact of body weight loss on single plasma TSH concentration measurements or the TSH response to TRH in obese humans have shown variable results.

Objective: The objective of this study was to investigate the effect of weight loss induced by caloric restriction on diurnal TSH concentrations and secretion in obese humans.

Design: This was a clinical, prospective, crossover study.

Setting: The study was conducted at the Clinical Research Center of Leiden University Medical Center.

Participants: Eleven obese premenopausal women (body mass index, 33.3 ± 0.7 kg/m²) were studied.

Intervention: The study intervention was weight loss (50% reduction overweight by caloric restriction).

Main Outcome Measure(s): Twenty-four-hour plasma TSH concentrations (10-min intervals) and the 24-h TSH secretion rate, calculated by a waveform-independent deconvolution technique (Pulse), were determined.

Results: The 24-h TSH secretion rate was significantly higher in obese women than in normal weight controls, and weight loss was accompanied by diminished TSH release (before weight loss, 43.4 ± 6.4 mU/liter·24 h; after weight loss, 34.4 ± 5.9 mU/liter·24 h; P = 0.02). Circulating free T₃ levels decreased after weight loss from 4.3 ± 0.19 to 3.8 ± 0.14 pmol/liter (P = 0.04). Differences in 24-h TSH release correlated positively with the decline of circulating leptin (r² = 0.62; P < 0.01).

Conclusions: Elevated TSH secretion in obese women is significantly reduced by diet-induced weight loss. Among various physiological cues, leptin may be involved in this phenomenon. The decreases in TSH and free T₃ may blunt energy expenditure in response to long-term calorie restriction, thereby frustrating weight loss attempts of obese individuals.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
THE HYPOTHALAMIC-PITUITARY-thyroid (HPT) axis regulates energy expenditure, oxygen consumption, and fuel metabolism. HPT axis disorders impact metabolic rate, thermogenesis, and body weight. Conversely, changes in body weight are accompanied by compensatory changes in energy expenditure (1), which may be brought about in part by adaptations of HPT axis activity.

All clinical studies evaluating the impact of body weight loss on the HPT axis have used single measurement of TSH, thyroid hormones, and/or TSH release in response to TRH as a measure of activity. Most studies suggest that weight loss reduces TSH concentrations and the TSH response to TRH, whereas others report unchanged plasma TSH or TRH-induced TSH responses in obese individuals after weight loss (2, 3, 4, 5, 6). Because plasma TSH concentrations are characterized by circadian fluctuations, adequate appreciation of the impact of body weight loss on TSH release requires frequent measurement of TSH over time. Because circulating thyroid hormone levels are relatively stable, determination in a single sample suffices (7).

We recently showed that diurnal TSH secretion is significantly enhanced in obese women (Kok, P., F. Roelfsema, and M. Frölich, unpublished observations), in whom the TSH secretion rate appears to be positively correlated with circulating leptin levels and body mass index (BMI). Other studies provide strong evidence that leptin stimulates TSH production in rodents and humans (8, 9). We studied the impact of body weight loss induced by caloric restriction and associated decline of circulating leptin levels on spontaneous diurnal TSH release in obese humans.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

Eleven healthy obese premenopausal women were enrolled after giving written informed consent for participation. A historical control group of 11 lean controls (BMI, 21.4 ± 0.5 kg/m²) of similar sex and age (obese, 35.8 ± 2.3; lean, 36.0 ± 1.8 yr; P = 0.95) was included. All subjects underwent medical screening, including medical history, physical examination, standard laboratory hematology, blood chemistry, and urine tests. Acute or chronic disease, smoking, weight change before the study (>3 kg in 3 months), and use of medication (including oral contraceptives) or iodine supplements were exclusion criteria for participation. Subjects had not been exposed to radio contrast dyes and did not have personal or family history of thyroid dysfunction. All participants had regular menstrual cycles.

Weight loss

Obese subjects started a weight loss program after the first study occasion to reduce their body weight by 50% of their overweight within a period of 4 months (range, 1.5–7 months) by dietary intervention, using a liquid very low calorie diet (VLCD) (2 MJ/d; 43% proteins, 15% fat, and 42% carbohydrates; 159 µg/d iodine; Modifast, Novartis, Veenendaal, The Netherlands), whereas physical activity level remained constant. Total body fat was quantified using bioelectrical impedance analysis (Bodystat, Douglas, Isle of Man, UK) and visceral/sc fat areas were assessed by magnetic resonance imaging before and after weight loss.

Clinical protocol

The protocol was approved by the medical ethics committee of the Leiden University Medical Center. All subjects were studied in the early follicular stage of their menstrual cycle. Obese women were studied before and after weight loss. To limit the putative direct effects of feeding/VLCD on thyroid hormone release (which tend to occur almost immediately), all subjects used a standard eucaloric diet (1980 kcal/8.3 MJ·d) as of 3 d before each admission until the end of blood sampling. Subjects were admitted to the research unit at 0800 h. One hour after insertion of an iv cannula into an antecubital vein, blood sampling started using a constant withdrawal pump (Conflo, Carmeda AB, Taeby, Sweden). Meals were served according to a fixed time schedule. No daytime naps were allowed. Lights were switched off at 2300 h. Vital signs were regularly recorded, and great care was taken not to disturb and touch patients while sampling blood during their sleep (no electroencephalogram sleep recording was performed).

Assays

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), calibrated against the World Health Organization Second Standard International Reference Preparation (80/558). The detection limit was 0.05 mU/liter, and the interassay variation coefficient was less than 5%. Leptin concentrations were determined by RIA (Linco Research, Inc., St. Charles, MO) with a detection limit of 0.5 µg/liter and an interassay coefficient of 6–7%. Total and free T₄ were measured using an automated system (Elecsys 2010, Roche, Almere, The Netherlands). Free T₃ was measured with a microparticle enzyme immunoassay on an Imx (Abbott Laboratories, Chicago, IL). Total T₃ and rT₃ was measured by an in-house RIA (Erasmus MC, Rotterdam, The Netherlands). Estradiol was determined by RIA (Diagnostic Systems Laboratory, Webster, TX).

Calculations and statistics

Cluster delineates characteristics of pulsatile hormone concentration profiles. We used a 2 x 1 cluster configuration (10).

The Pulse algorithm is a waveform-independent deconvolution method that can be used for calculation of hormonal secretion based on plasma hormone concentration time series, without specifying the shape, number, and time of secretory events, and was used to quantify mean 24-h TSH secretion (11). TSH disappearance from plasma is best described by a two-compartment model (fast component half-life, 18 min; slow component, 90 min; fractional contribution of the slow component, 32%; data provided by J. D. Veldhuis, Mayo Clinic, Rochester, MN). The approximate entropy statistic assigns a nonnegative number to time series data, to quantify the regularity of these data (7). Nyctohemeral characteristics of TSH concentration patterns were determined using Clevelands’ robust regression technique (7). Data were statistically analyzed using parametric or nonparametric test when appropriate. Multiple regression analysis was performed to estimate the correlation between differences of these parameters vs. differences of 24-h TSH secretion before and after weight loss.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

All subjects were clinically euthyroid. BMI, total body fat, and visceral and sc fat areas were significantly reduced after weight loss (Table 1). T₄ (free T₄) levels in lean subjects were 16.4 ± 0.5 pmol/liter (P = 0.09 vs. obese before VLCD). Free T₃ levels were positively related to BMI in all subjects (r² = 0.51; P = 0.01), whereas BMI and total T₃ were not related (r² = 0.19; P = 0.19). Total and free T₃ were significantly reduced after weight loss. Differences in free or total T₃ levels did not correlate with changes in body composition parameters before and after weight loss.

Mean 24-h TSH concentration, mean peak height, and mean peak area were significantly lower, whereas peak frequency was significantly increased after weight loss. Nadir concentration and peak width were not significantly altered by weight reduction (Table 2). Mean 24-h TSH secretion was significantly reduced in the obese women after weight loss (Table 2). The duration of the diet period did not correlate with differences in TSH secretion (r² = 0.12; P = 0.29). After weight loss, TSH concentration and secretion parameters did not differ significantly from those in lean controls, except for pulse width, peak area, and pulse frequency. Figure 1 shows the mean 24-h plasma TSH concentrations. Approximate entropy ratios were similar before and after weight loss (0.51 ± 0.03 vs. 0.54 ± 0.04, respectively; P = 0.29) and were similar in obese and lean women (0.52 ± 0.04; P = 0.74). Clock-times of the acrophase were identical before and after weight loss (0020 h ± 30 min vs. 0010 h ± 30 min, respectively; P = 0.82) and were similar in obese and lean subjects (0130 h ± 50 min; P = 0.16).

View larger version (40K): [in this window] [in a new window]   FIG. 1. Mean serum TSH concentration time series of the obese subjects before (black circle) and after weight loss (gray circle) and mean serum TSH concentration time series of the historical control subjects (white circle). Data reflect blood sampling every 10 min for 24 h. Sampling starts at 0900 h. Lights were switched off, and subjects went to sleep at 2300 until 0730 h next morning (vertical gray bar). Sleep was not interrupted.

Mean 24-h leptin concentrations were significantly reduced after weight loss in obese women (P = 0.22 vs. leptin in lean subjects; 13.3 ± 2.5 µg/liter). Multiple regression analysis, including body weight, BMI, percent total body fat, and mean 24-h leptin concentrations as independent variables revealed that the difference in 24-h TSH secretion was positively correlated with differences in mean 24-h leptin concentrations (P < 0.01; partial correlation r² = 0.62; Fig. 2) and with differences in body weight (P = 0.01) and BMI (P < 0.01).

View larger version (11K): [in this window] [in a new window]   FIG. 2. Differences in TSH secretion were significantly positively related to differences in mean 24-h leptin concentrations (r2 = 0.62; P < 0.01) before and after weight loss in obese women. Differences in TSH secretion were logarithmic transformed. The range of differences in TSH secretion was –4.0 to –49.9 mU/liter·24 h. Twenty-four-hour TSH secretion is calculated per liter distribution volume.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Previous studies have evaluated the impact of weight loss on the HPT axis using a single plasma TSH concentration and/or TSH release in response to TRH as a measure of activity. Most of these studies indicate that weight loss lowers TSH concentrations and blunts the TRH-induced TSH response (2, 3, 4, 5, 6), which is in line with the present results.

Our subjects used a eucaloric diet for 3 d before each study to limit the putative impact of calorie restriction on TSH release. Although dietary intervention tends to impact circulating TSH rather quickly (i.e. within 3 d) (12), we cannot exclude the possibility that the decline in TSH and T₃ we observed was due to persistent effects of the VLCD rather than to the loss of body weight.

Thyroid hormones control pituitary TSH release by feedback inhibition at the pituitary and hypothalamic level (for review, see Ref.13). In the present study, free T₄ and T₄ remained unchanged, whereas free T₃ and T₃ were lower after weight loss, which is in line with previous studies (14, 15). Thus, other factors modulate TSH production so as to decrease in response to weight loss in obese women.

Several studies in rodents and humans provide strong evidence that leptin stimulates TSH production (8, 9). In our study, the reduction of 24-h TSH secretion correlated with the decline of mean 24-h leptin concentration in response to weight loss. In concert, these data support the idea that leptin plays a role in the control of pituitary TSH release in (obese) humans.

Alternatively, activation of dopamine D2 receptors (D2R) may be involved. TSH release is inhibited by D2R activity (13), and D2R binding sites in the brain are reduced in obese humans (16). Calorie restriction and weight loss are accompanied by increased D2R signaling in animals (17) and probably also in humans (18). Thus, reduced central D2R neurotransmission may unleash TSH release in obese humans, and up-regulation of D2R tone in response to weight loss may then restore TSH secretion to normal.

Finally, it has been reported that exogenous estrogens raise TSH concentrations (19), and estradiol levels were significantly lower after weight loss in the present study, which has been documented previously (20). However, we did not find a significant relation between changes in TSH secretion and estradiol concentrations in response to weight loss, which argues against an important role of this hormone in the modulation of HPT axis activity.

Whatever the underlying mechanism, changes in HPT activity in response to body weight loss in obese humans may be of clinical and physiological relevance. Because thyroid hormones stimulate resting energy expenditure and basal metabolic rate (for review, see Ref.13), a decline of TSH release and T₃ concentrations may contribute to the compensatory reductions of energy expenditure and catabolism that typically accompany weight loss (21). Although such neuroendocrine adaptation surely protected us against the perils of famine in ancient times, it may hamper weight loss attempts in current times of plenty.

It seems important to emphasize that the waveform- dependent deconvolution technique, we employed requires a priori definition of TSH clearance. Therefore, we cannot rule out the possibility that changes in plasma TSH clearance contribute to the decline in circulating TSH levels that we observed in response to weight loss.

In conclusion, the elevated diurnal TSH secretion rate in obese premenopausal women is blunted in response to body weight loss induced by long-term caloric restriction, which is accompanied by a diminution of circulating T₃. The concomitant decline in circulating leptin levels or changes in central dopamine D2R neurotransmission may be among the regulatory cues involved in this neuroendocrine adaptation that potentially frustrate obese humans in their attempts to lose weight.

	Acknowledgments

 
We thank Prof. T. J. Visser (Erasmus Medical Center, Rotterdam, The Netherlands), the analysts of the Clinical Chemistry Department of Leiden University Medical Center (M. van Dijk-Besling and J. H. G. Haasnoot-van der Bent), and the research assistants of the Clinical Research Center of the General Internal Medicine Department of Leiden University Medical Center (E. J. M. Ladan-Eijgenraam and I. A. Sierat-van der Steen) for their assistance during the study.

	Footnotes

 
First Published Online May 24, 2005

Abbreviations: BMI, Body mass index; D2R, dopamine D2 receptor; HPT, hypothalamic-pituitary-thyroid; VLCD, very low caloric diet.

Received April 27, 2005.

Accepted May 12, 2005.

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