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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2008-0001
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 9 3455-3461
Copyright © 2008 by The Endocrine Society

Short-Term Treatment with Bromocriptine Improves Impaired Circadian Growth Hormone Secretion in Obese Premenopausal Women

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

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

Address all correspondence and requests for reprints to: Professor H. Pijl, M.D., Ph.D., 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: A profound reduction of spontaneous as well as stimulated GH secretion has been consistently observed in obesity. Dopamine promotes GH release through activation of dopamine D2 receptors (D2Rs). Dopamine D2R availability in the brain is reduced in obese humans in proportion to body adiposity. We hypothesized that impaired dopamine D2R signaling is mechanistically involved in the deficient GH secretion associated with obesity.

Objective: To test this hypothesis, we studied the effect of short-term bromocriptine (B) (a D2R agonist) treatment on spontaneous 24-h GH secretion in obese women, while body weight and caloric intake remained constant.

Design: This was a prospective, fixed order, cross-over study.

Setting: The study was performed in the Clinical Research Center at Leiden University Medical Center.

Participants: There were 18 healthy obese women (body mass index 33.2 ± 0.6 kg/m2) studied twice in the early follicular phase of their menstrual cycle.

Intervention(s): Eight days of treatment with B and placebo (Pl) was performed.

Main Outcome Measure(s): Blood was collected during 24 h at 10-min intervals for determination of GH concentrations. GH secretion parameters were calculated using deconvolution analysis.

Results: Short-term treatment with B significantly enhanced diurnal GH secretion (Pl 121.4 ± 16.4 vs. B 155.4 ± 15.2 µg/litervolume of distribution·24 h; P = 0.01), whereas IGF-I concentrations remained constant (Pl 22.4 ± 2.4 vs. B 21.8 ± 1.6 nmol/liter; P = 0.928).

Conclusions: Activation of dopamine D2Rs by B favorably affects impaired nyctohemeral GH secretion in obese women. Reduced dopaminergic neuronal signaling might be involved in the pathogenesis of obesity associated hyposomatotropism.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
Spontaneous and secretagogue-induced GH secretion is profoundly reduced in obese humans (1, 2, 3, 4, 5, 6, 7, 8, 9, 10). The mechanistic underpinnings of this neuroendocrine anomaly remain elusive.

Dopamine is involved in the regulation of GH release. Although dopamine agonists have therapeutically been used to suppress GH release in patients with acromegaly, several clinical studies provide evidence for a stimulatory effect of dopaminergic neurotransmission on GH secretion in healthy humans. For example, either dopamine infusion or treatment with dopamine 2 receptor agonists promotes spontaneous as well as secretagogue-induced GH release in normal man (11, 12, 13, 14, 15, 16). Dopamine receptors are present on human somatotrophs, and experimental studies in rodents suggest that the stimulatory effect of dopamine on GH release is mediated by dopamine D2 receptors (D2Rs). For example, D2R knockout mice have reduced somatotroph cell mass and secretory activity (17, 18).

D2R binding capacity in the brain of obese humans is reduced in proportion to body mass index (BMI) (19). Dietary restriction and weight loss are accompanied by increased dopaminergic signaling in animals (20, 21), and indirect evidence suggests that calorie restriction also reinforces central dopaminergic tone in obese humans (22, 23). Thus, these data suggest that food restriction and body weight loss restore central dopaminergic tone in obese humans, at least to a certain extent. Interestingly, weight loss also partially restores GH secretion in obese humans (10).

Because D2R mediated neurotransmission promotes GH release, deficient dopaminergic signaling may underlie obesity associated hyposomatotropism. We postulated that short-term treatment with a D2R agonist [bromocriptine (B)] would increase spontaneous GH secretion in obese humans.

To test this hypothesis, we measured 24-h plasma GH concentrations and calculated spontaneous GH secretion rate in 18 otherwise healthy obese women. All subjects were treated with B and placebo (Pl) for 8 d in a fixed order cross-over study design. We previously showed that B significantly affects various metabolic and endocrine parameters that may affect GH secretion, including circulating leptin, insulin, glucose, and free fatty acid (FFA) levels [previously published data by Kok et al. (24, 25)]. Therefore, we also sought to determine the relationship between changes of these parameters and mean 24-h GH concentration in response to B treatment in the obese women enrolled in this study.


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

Subjects were recruited through advertisements in local newspapers. Before participation, all subjects underwent medical screening, including medical history taking, physical examination, standard laboratory hematology, blood chemistry, and urine tests. Acute or chronic disease, depression (present or in history), head trauma, smoking, alcohol abuse, recent trans-meridian flights, night-shift work, weight change before the study (>5 kg in 3 months), recent blood donation, or participation in another clinical trial (<3 months), and use of medication (including oral contraceptives) were exclusion criteria for participation. All participants were required to have regular menstrual cycles. There were 18 healthy obese premenopausal women (BMI 30–35 kg/m2, mean age 37.5 ± 1.7 yr, range 22–51 yr) enrolled in this study. All study occasions were performed in the early follicular phase of the menstrual cycle.

Clinical protocol

The protocol was approved by the Medical Ethics Committee of the Leiden University Medical Center and was performed according to the Helsinki declaration. All subjects gave written acknowledgment of informed consent for participation. They were admitted to the Clinical Research Unit of the Department of General Internal Medicine in the early follicular stage of their menstrual cycle. Subjects were studied twice with an interval of 4 wk, in which body weight remained stable, and subjects were instructed to keep their physical activity level constant. The clinical setup was the same during both occasions apart from the subject receiving the alternative treatment (B or Pl). Subjects were admitted to the research center at 0700 h. A cannula for blood sampling was inserted into an antecubital vein, which was attached to a three-way stopcock and kept patent by a continuous 0.9% NaCl and heparin (1 U/ml) infusion (500 ml/24 h). Blood samples for basal parameters were withdrawn, and 24-h blood sampling was started. Blood was collected with S-monovetten (Sarstedt, Etten-Leur, The Netherlands) at 10-min intervals for determination of GH concentrations. Blood samples for the measurements of plasma insulin, prolactin (PRL), and glucose concentrations were taken at 10-min intervals, leptin was measured at 20-min intervals, and hourly withdrawals were performed for the assessment of plasma FFA levels. Subjects remained recumbent during the blood-sampling period, except for bathroom visits. No daytime naps were allowed. Well-being and vital signs were recorded at regular time intervals (hourly). Meals were served according to a fixed time schedule and consumed within limited time periods. Lights were switched off at 2300 h, and great care was taken not to disturb and touch subjects during withdrawal of blood samples while they were sleeping. No electroencephalogram sleep registration was performed. Lights were switched on, and subjects were awakened at 0730 h in the morning.

Drug treatment

Subjects were assigned to B or Pl treatment for a period of 8 d in a fixed order cross-over design. All subjects received Pl during the first intervention period. A 4-wk time interval separated study occasions. A dose of 2.5 mg B was prescribed on the first day. Thereafter, drug or Pl was taken twice daily (totaling 5.0 mg daily) at 0800 and 2000 h for 7 d. On the first day of B treatment, 10 participants had gastrointestinal complaints (nausea, vomiting), which disappeared after 1 d. Although this study design still has an inherent risk of observer bias, this design was used to avoid potential cross-over effects of B treatment. All assays and analyses were done by co-workers who were blinded to the type of intervention.

Diet

All subjects were prescribed a standard eucaloric diet, as from 1 d before admission until the end of each study occasion. The caloric content and macronutrient composition of the diet were exactly the same at both study occasions. Intake of alcohol and caffeine/theine containing beverages was not allowed. Meals were served according to a fixed time schedule (breakfast 0930 h, lunch 1300 h, and dinner 1830 h) and were consumed within limited time periods. No dietary restrictions were imposed between both study occasions.

Assays

Samples of each subject were determined in the same assay run. GH concentrations were measured with a sensitive time-resolved fluoroimmunoassay (Wallac, Turku, Finland) specific for the 22-kDa GH protein. The assay uses recombinant human GH as standard (Genotropin; Pharmacia & Upjohn, Uppsala, Sweden), which is calibrated against World Health Organization First International Reference Preparation (80–505). The limit of detection is 0.03 µg/liter. Intraassay coefficients of variation (CVs) were 1.6–8.4% in the concentration range 0.26–47 mU /liter, with corresponding interassay CVs of 2.0–9.9%. The total serum IGF-I concentration was determined by RIA after extraction and purification on ODS-silica columns (Incstar Corp., Stillwater, MN). The interassay CV was less than 11.8%. The detection limit was 1.5 nmol/liter. Plasma leptin concentrations were determined by RIA (LINCO Research, Inc., St. Charles, MO). The detection limit was 0.5 ng/liter, and the interassay CVs were 3.6–6.8%. The PRL immunofluorometric assay was calibrated against the third World Health Organization standard: 84/500, 1 ng/ml = 36 mU/liter. The intraassay CV varies from 3.0–5.2%, and interassay CV is 3.4–6.2%, in the concentration range from 0.1–250 µg/liter. Estradiol concentrations were determined by RIA (Diagnostic Systems Laboratories, Inc., Webster, TX). The detection limit was 10 pmol/liter, and the interassay CV was 5.1–8.1%. Serum insulin was measured with immunoradiometric assay (Biosource Europe, Nivelles, Belgium), with a detection limit of 2 µU/liter and interassay CV of 4.4–5.9%. Plasma FFA levels were determined using a NEFA-C Free Fatty acid kit (Wako Chemicals GmbH, Neuss, Germany), with a detection limit of 30 µmol/liter and interassay CV of 2.6%. Daylong blood glucose concentrations were assessed using a blood glucose analyzer (Accutrend; Boehringer, Mannheim, Germany). Basal serum glucose was measured using a fully automated Modular P 800 (Hitachi, Tokyo, Japan), and free T4 concentrations were estimated using electrochemoluminescence immunoassay (Elecsys 2010; Roche Diagnostics Nederland BV, Almere, Netherlands).

Calculations and statistics

Deconvolution method for analyzing pulsatile GH secretion Hormonal secretion profiles were analyzed using a recently developed deconvolution method (26). The fully automated MATLAB program (The MathWorks, Inc., Natick, MA) uses the following strategies to estimate hormone secretion rates. First, the program detrends the plasma hormone concentration time series and normalizes values to the unit interval (0, 1) (27). Second, multiple potential pulse-time sets are created by a smoothing process derived from a nonlinear adaptation of the heat-diffusion equation. Third, the program estimates all secretion and elimination rates simultaneously for each of the multiple candidate pulse-time sets. The model structure for secretion and elimination includes parameters for basal secretion (β0), two half-lives ({alpha}1, {alpha}2), secretory-burst mass ({eta}0, {eta}1), random effects on pulse mass ({sigma}A), procedural/measurement error ({epsilon}), and a three-component flexible waveform shape (β1, β2, β3). Finally, model selection is performed to distinguish among the candidate pulse-time sets using the Akaike information (28). Secretion and elimination parameters include: burst frequency (number per 24 h) ({lambda} of Weibull distribution), the regularity of interpulse interval ({gamma} of Weibull), the fast and slow half-lives (min), basal and pulsatile secretion rates (µg/liter·24 h), mass per pulse concentration units, and the time delay (min) to maximal secretion from burst onset (model of waveform) (29).

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 (30). Higher ApEn values denote greater relative randomness of hormone patterns. 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 (31).

Statistics Statistical analysis was performed using SPSS (version 11.5; SPSS, Inc., Chicago, IL). Results of both study groups with/without B were compared after logarithmic transformation using a paired-Student’s t test. Significance level was set at 0.05. Data are presented as mean ± SEM. Multiple regression analysis was performed to estimate the correlation between changes in metabolic parameters (mean 24 h glucose, insulin, and FFA plasma concentrations) and mean 24-h leptin concentrations vs. changes of mean 24-h GH concentrations induced by B treatment in the obese subjects. Differences were calculated subtracting values during B treatment from values during Pl treatment. Negative differences reflect a decrease, and positive differences reflect an increase induced by B treatment of the parameter.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Screening parameters at recruitment

There were 18 obese subjects enrolled in the study. The mean age of the subjects was 37.5 ± 1.7 yr (range 22–51). Subjects had a mean body weight of 93.9 ± 2.6 kg (range 81.2–124.1), which remained stable from 3 months before until the end of the study period. They had a BMI of 33.2 ± 0.6 kg/m2 (range 30.1–40.5) and a total percent body fat of 39.6 ± 0.8% (range 32.1–44.8). Mean fasting glucose concentration was 5.0 ± 0.1 mmol/liter (range 4.2–6.3), insulin 15.3 ± 1.7 mU/liter (range 7–28), glycosylated hemoglobin 4.7 ± 0.1% (range 3.9–5.3), total cholesterol 4.7 ± 0.2 mmol/liter (range 3.7–5.8), low-density lipoprotein cholesterol 2.99 ± 1.57 mmol/liter (range 2.03–4.00), and high-density lipoprotein cholesterol 1.54 ± 0.08 mmol/liter (range 1.03–2.32). These parameters and blood pressure (systolic and diastolic) were similar (not significantly different) at screening and at the first actual study occasion (Pl treatment).

Basal measurements

Basal measurements were performed at the beginning of each study occasion, immediately before the blood sampling period started. Body weight and BMI were similar during Pl and B treatment (weight Pl 94.1 ± 2.5 vs. B 94.4 ± 2.5 kg, P = 0.33; and BMI Pl 33.2 ± 0.6 vs. B 33.3 ± 0.6 kg/m2, P = 0.35). All subjects had regular menstrual cycles and were studied in the early follicular phase of their menstrual cycle (estradiol Pl 163 ± 21 vs. B 209 ± 21 pmol/liter, P = 0.10; and progesterone Pl 2.13 ± 0.64 vs. B 2.94 ± 1.13 nmol/liter, P = 0.56). Mean 24-h PRL concentrations were significantly reduced by B (PRL Pl 8.27 ± 0.37 vs. B 1.42 ± 0.34 µg/liter; P < 0.001). Subjects were euthyroid (free T4 levels Pl 14.6 ± 0.4 vs. B 14.4 ± 0.4 pmol/liter; P = 0.56).

Effect of B on GH secretion parameters

B treatment significantly increased pulsatile and total GH secretion, whereas all the other kinetic/secretion characteristics remained unaltered. A graphical illustration of the 24-h GH concentration plots (mean of all subjects) vs. clock time is shown in Fig. 1Go. An overview of GH secretory and kinetic parameters during Pl and B treatment is given in Table 1Go. Figure 2Go provides a graphical illustration of various features of circadian GH secretion during Pl and B treatment. IGF-I concentrations were not affected by B treatment (Pl 22.4 ± 2.4 vs. B 21.8 ± 1.6 nmol/liter; P = 0.928). The ApEn of serum GH concentration series was significantly higher after B treatment compared with Pl (Pl 0.623 ± 0.047 vs. B 0.742 ± 0.054; P = 0.015) (Fig. 3Go).


Figure 1
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  		FIG. 1. Median diurnal serum GH concentration time series of obese subjects (n = 18) during Pl (-•-) and B treatment (-{circ}-). Data reflect sampling of blood every 10 min for 24 h. Blood sampling started at 0900 h. Lights were switched off, and subjects went to sleep at 2300 h until 0730 h the next morning, when lights were switched on (gray horizontal bar indicates lights-off period).

 

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  		TABLE 1. Features of 24-h GH secretion

 

Figure 2
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  		FIG. 2. Features of diurnal GH secretion in obese women during Pl (black bars) and B treatment (open bars). Error bars of the box plot represent SEM. *P < 0.05 obese vs. lean women. Statistical analysis was performed using paired samples t test of logarithmic data. NS, Not significant.

 

Figure 3
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  		FIG. 3. Regularity of serum GH concentration-time series in obese women during Pl and B treatment. Higher absolute ApEn values denote greater relative randomness of hormone patterns.

 
GH secretion vs. metabolic parameters, insulin, and leptin

The impact of B treatment on metabolic parameters and leptin in the same women was previously reported (24, 25). In fact, these earlier publications showed that 24-h glucose, insulin, and leptin concentrations were significantly reduced, whereas FFAs were enhanced after B treatment. Here, we found that the range of the differences in mean 24-h GH concentrations in response to B was –0.37 to 2.57 µg/liter (a negative difference reflects a decrease of GH concentration during B treatment). Multiple regression analysis, including differences ({Delta}) of mean 24-h glucose, insulin, FFA, and mean 24-h leptin concentrations as independent variables, revealed that none of the changes of these parameters was significantly correlated with differences in mean 24-h GH concentrations in response to B treatment: mean 24-h insulin (range {Delta} insulin –34.16 to 6.97 mU/liter; R2 = –0.209; P = 0.472); mean 24-h glucose (range {Delta} glucose –1.22 to 0.72 mmol/liter; R2 = 0.372; P = 0.171); mean 24-h FFA (range {Delta} FFA –0.04 to 0.48 mmol/liter; R2 = –0.011; P = 0.970); and mean 24-h leptin concentrations (range {Delta} leptin –14.7 to 8.2 ng/liter; R2 = –0.067; P = 0.821).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This is the first study documenting a stimulatory effect of D2R activation by B on spontaneous circadian GH secretion in obese women. Interestingly, B appears to specifically enhance pulsatile (not basal) GH release, and it is precisely this component of the GH release process that is blunted in obese humans (7, 32).

Dopamine receptors are present on human somatotrophs. Experimental animal studies indicate that the stimulatory effect of dopamine on GH release occurs through activation of dopamine D2Rs (17, 18). Various studies in healthy, nonobese humans have also shown that activation of D2R elevates spontaneous and secretagogue induced plasma GH levels. D2R binding capacity in the brain of obese humans is reduced in proportion to BMI (19), and GH secretion is reduced in proportion to body fat mass (10). Our data suggest that these two pathophysiological features of obese individuals are mechanistically linked. Our data also show that B elevates mean ApEn scores of plasma GH concentration profiles of the obese humans. Notably, ApEn scores were decreased during B treatment in four obese women. The reason why these women deviate from the overall picture remains elusive. The rate at which any hormone is secreted is the net result of positive feed forward drive and negative feedback restraint. Reinforcement of feed forward inputs generally elevates plasma hormone concentrations and their ApEn score (33, 34). Thus, the present results are consistent with the postulate that B reinforces feed forward inputs to stimulate GH release.

It is interesting to note that obesity is marked by deficient pulsatile, but not basal GH secretion (7, 32). We now report that B specifically increases this component of the GH release process. Pulsatile GH secretion is primarily controlled by GHRH (35). Thus, B probably reinforces GHRH feed forward drive (by enhancing somatotroph sensitivity and/or stimulating hypothalamic release) to promote pulsatile pituitary GH output. The reason why plasma IGF-I concentrations did not increase concomitantly remains unclear. Perhaps the short duration of intervention plays a role. In this context it should be emphasized that, although B significantly enhanced GH secretion in the obese subject, it did not fully restore 24-h GH production toward levels we previously observed in normal weight controls (36). Furthermore, we previously mentioned that older studies have shown that stimulation of dopaminergic signaling increases GH secretion. However, none of these studies addressed the effect of B on 24-h GH secretion in normal subjects. Thus, it remains unclear whether the stimulatory effect of B might be more pronounced in obese women compared with normal weight controls. Finally, one should note that the study had a fixed order study design. Consequently, the observed changes could possibly be due to a bias in study participation. It is possible that during the second period, the subjects got more used to the procedure and slept better, which, thus, contributed to increased GH pulsatility.

Apart from D2R mediated dopamine signals, various endocrine and metabolic cues can also modulate GH secretion. In previous papers we have reported that B favorably affects multiple components of the metabolic syndrome in the same women as described here (24, 25). A number of these components, including circulating glucose, FFA, insulin, and leptin, are known to impact on GH release, and it seemed important to consider their role in the stimulatory effect of B on GH release reported here. Insulin and glucose blunt GH release (37, 38), and B significantly lowers plasma insulin and glucose concentrations (25). In addition, leptin stimulates GH secretion in rodents (39), GH secretion is inversely correlated with serum leptin concentrations in humans (40, 41), and circulating leptin levels were significantly reduced by B (25). Thus, either one of these metabolic and endocrine cues could mediate the effects of B on GH secretion. However, no significant correlation between changes in 24-h GH concentrations and changes in plasma levels of any of these potential modulators was found in response to B, which obviously argues against an important modulatory role of any of them. Finally, FFAs suppress GH release in humans and animals (42, 43, 44). The fact that B treatment increased circulating FFAs (25) does not support the postulate that FFAs are involved in the stimulatory effect of the drug on GH.

A considerable amount of data from animal and clinical studies suggests that reduced dopaminergic neurotransmission is involved in the pathogenesis of obesity and the metabolic syndrome (for review, see Ref. 45). For example, reduced dopaminergic neurotransmission in suprachiasmatic nuclei precedes the development of obesity and insulin resistance both in hibernating animals (46) and in various animal models of nonseasonal obesity (45), whereas treatment with the dopamine D2R agonist B effectively redirects the obese insulin-resistant state toward the lean insulin-sensitive state in these animals (47, 48, 49, 50, 51, 52, 53). Moreover, clinical studies show that treatment with D2R antagonists induces obesity and diabetes mellitus type 2, whereas D2R activation ameliorates the metabolic profile in obese nondiabetic and diabetic humans (45). Thus, deficient D2R-mediated dopaminergic neurotransmission may contribute to these metabolic anomalies associated with obesity.

The present findings suggest that hyposomatotropism may be one of the endocrine messengers linking deficient D2R binding capacity in the brain and disruption of carbohydrate and lipid metabolism in peripheral tissues in obese humans. GH deficiency is associated with (abdominal) obesity and the metabolic syndrome (10). Adequate GH substitution restores the healthy metabolic balance (54, 55). GH particularly promotes lipolysis, and hyposomatotropism, therefore, shifts the balance between lipid breakdown and lipid storage in adipocytes toward storage (56). Lipid storage in the visceral depot then impacts on glucose metabolism to induce glucose intolerance. We speculate that deficient D2R mediated neurotransmission in the brain may lead to metabolic anomalies via its impact on GH secretion.

We discussed the role of deficient D2R signaling in the impaired GH release in obese individuals. However, GH secretion is influenced by numerous other regulatory cues. For example, serotonin, GHRH, endorphin, or somatostatin (for review, see Ref. 57) are involved in the regulation of GH release. Several of these neurohormones probably partake in the mechanism(s) driving anomalous GH release in obesity (58, 59). Furthermore, an anatomical basis for a possible interaction between these factors, i.e. GHRH or catecholamine neurons, and the dopaminergic system, has been provided in experimental animal studies (60, 61, 62). Thus, it is conceivable that indirect changes of these systems are involved in the effect of B on GH release.

In conclusion, the present study shows that short-term B treatment partially restores the deficient spontaneous circadian GH secretion in obese women. These data suggest that reduced dopaminergic neurotransmission is involved in the pathogenesis of obesity associated hyposomatotropism.


   Acknowledgments
 
We thank R. J. W. de Wilde, the technicians 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) for their assistance during the performance of the study.


   Footnotes
 
Disclosure Statement: The authors have nothing to disclose.

First Published Online June 17, 2008

Abbreviations: ApEn, Approximate entropy; B, bromocriptine; BMI, body mass index; CV, coefficient of variation; D2R, D2 receptor; FFA, free fatty acid; Pl, placebo; PRL, prolactin.

Received January 2, 2008.

Accepted June 9, 2008.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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P. Kok, F. Roelfsema, M. Frolich, J. van Pelt, A. E. Meinders, and H. Pijl
Bromocriptine Reduces Augmented Thyrotropin Secretion in Obese Premenopausal Women
J. Clin. Endocrinol. Metab., April 1, 2009; 94(4): 1176 - 1181.
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