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Original Studies |
Department of Endocrinology (M) and Center for Eating Disorders, Odense University Hospital (R.K.S., J.H., J.K., C.H.), DK-5000 Odense, Denmark; the Department of Internal Medicine, National Science Foundation Center for Biological Timing, University of Virginia Health Sciences Center (J.D.V.), Charlottesville, Virginia 22908; Medical Department M (Endocrinology and Diabetes), Medical Research Laboratory and Institute of Experimental Clinical Research, University Hospital of Aarhus (A.F.), DK-8000 Aarhus, Denmark; the Department of Medical Physiology, Panum Institute, University of Copenhagen (J.V.), DK-2200 Copenhagen, Denmark; and the Department of Clinical Chemistry, Sonderborg Hospital (O.G.K.), DK-6400 Sonderborg, Denmark
Address all correspondence and requests for reprints to: René Klinkby Støving, M.D., Department of Endocrinology (M), Odense University Hospital, DK- 5000 Odense C, Denmark.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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The deconvolution-estimated half-life of GH was not altered in the AN patients. The pituitary GH secretory burst frequency, burst mass, and burst duration were each significantly increased in women with AN compared to those in normal weight women. A 4-fold increase in daily pulsatile GH secretion was accompanied by a 20-fold increase in basal (nonpulsatile) GH secretion. There were significant negative correlations between BMI and the basal as well as pulsatile GH secretion rates. Moreover, AN patients exhibited significantly greater GH approximate entropy scores than the controls, denoting marked irregularity of the GH release process. In contrast to previous reports in healthy fasting subjects, cortisol levels in AN patients were positively correlated to GH secretion rates. Leptin levels were significantly inversely correlated to the pulsatile, but not the basal, GH secretion rate.
The present data demonstrate augmented basal as well as pulsatile GH secretion with disruption of the orderliness of the GH release process in AN. Accordingly, GH secretion in AN probably reflects altered neuroendocrine feedback regulation, e.g. associated with increased hypothalamic GHRH discharge superimposed on reduced hypothalamic somatostatinergic tone.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Basal concentrations (8) and GHRH-stimulated (9) GH release are increased in the major proportion of patients with AN. In anorectic patients, increased hypothalamic cholinergic activity has been inferred, with subsequently decreased somatostatinergic inhibition (10). By combining GHRH with an acetylcholinesterase inhibitor, pyridostigmine, the influence of somatostatin (SRIH) can be minimized (11). Data from this test combination suggest that the GH hypersecretion in AN reflects decreased somatostatinergic inhibition rather than increased stimulation from GHRH (12).
Although the metabolic effects of GH are known to be related to its pulsatile secretory pattern (13), detailed analysis of GH pulsatility in AN has only been performed in one study, in which the researchers performed nocturnal blood sampling in seven patients with AN (14). This study (14) suggested that the enhanced GH secretion in AN is largely due to increased nonpulsatile secretion. However, the analysis was performed by the Cluster algorithm, which provides limited information on underlying neuroendocrine secretory events, because discrete pulse detection does not account for the influence of GH clearance (15). Techniques, such as deconvolution analysis, which is designed to mathematically remove the impact of hormone kinetics and thereby uncover the pituitary GH secretory events, and approximate entropy (ApEn), which quantifies serial irregularity of hormone concentration pattern not reflected in pulsatility measurements, have not been applied to investigate GH axis pathophysiology in AN patients. Evaluating abnormal hormonal secretion by these tools may prove to be of diagnostic as well as prognostic value in handling AN. Therefore, we performed blood sampling at 20-min intervals for 24 h to evaluate spontaneous GH secretion using the foregoing new tools to explicit alterations in GH secretory control and serial irregularity. The pulsatile and entropic data were related to BMI and to serum levels of potential feedback regulatory hormones.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We studied 8 women with AN and 11 healthy age-matched women as
controls. The clinical and biochemical characteristics of the subjects
are summarized in Table 1
. The patients
met the diagnostic criteria for AN, according to the DSM-IV (1).
Duration of disease was for all patients more than 1 yr (range, 1–20
yr). None of the patients had received any drug therapy for at least 6
months before entering the study. All patients were hospitalized and
rehydrated orally for at least 3 days before the 24-h blood sampling.
During this prestudy stay as well as during the 24-h blood sampling,
the patients were offered a standardized menu at 0830, 1200, and
1730 h and snacks between meals at 1500 and 2000 h. The diet
contained between 7000–8000 kJ/day, 30% from lipid, 52–55% from
complex carbohydrates, and 15–18% from proteins. No physical exercise
was carried out, and the patients were resting in bed at least 1 h
after each meal. The participants were not allowed to sleep during the
day, but were allowed to sit or walk about. In the normohydrated
condition, all patients had weight changes of less than 5% in the last
week before the serial blood sampling. The controls were not receiving
any medication, and they all passed a physical examination and routine
laboratory screening, including serum concentrations of LH, FSH,
estradiol, total T3, fasting blood glucose, and insulin.
All of the control subjects had regular menstrual cycles, and the blood
sampling took place during the follicular stage of the cycle (days
2–8). The controls met at the hospital at 0700 h, 2 h before
the start of blood sampling. They were offered the same standardized
menu and were permitted the same physical activity regimen as mentioned
above.
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Four patients who gained weight from a mean BMI of 14.9 ± 0.7 to 17.3 ± 0.9 kg/m2 were restudied after 3 months. Four patients were not restudied, because they either failed to gain weight or were medicated. The study was approved by the local ethical committee, and the participants signed informed consent. All participants were more than 18 yr of age. It was explained to each patient that the study itself would not provide benefit to herself, although all data would be made available and explained upon request.
Hormone assays
All blood samples were allowed to clot at room
temperature, subsequently centrifuged, and stored at approximately -20
C until the assay. Serum GH was measured in duplicate by a two-site
fluoroimmunometric assay based on the direct sandwich technique, in
which two monoclonal antibodies are directed against two separate
antigenic determinants on the 22-kDa human GH molecule with europium as
the reporter molecule (Delfia, Wallac Oy, Turku, Finland). The level of
detection is 0.03 mU/L (
0.01 µg/L). The intra- and interassay
coefficients of variation (CVs) at 0.5 mU/L were 5% and 8%,
respectively, and they were 2% and 4%, respectively, at 18 mU/L.
Conversion of milliunits per L to micrograms per L is method dependent,
but approximately a factor 2.5–3.0. Serum IGF-I was determined after
acid-ethanol extraction using a noncompetitive time-resolved monoclonal
immunofluorometric assay, as previously described (16). Serum
IGF-binding protein-3 (IGFBP-3) was measured in duplicate by
immunoradiometric assay (<Diagnostic System Laboratories,
Inc., Webster, TX). Serum IGFBP-1 was determined in duplicate by
an enzyme-linked immunosorbent assay (Medix Biochemica, Kauniainen,
Finland). Serum/urinary cortisol was measured in duplicate with a
competitive RIA from Orion Diagnostica (Hellebaek, Denmark). The
detection limit was 5 nmol/L, the intraassay CV at 300 nmol/L was 2.5%
for serum and 2.8% for urine, and the interassay CV was 5.2% at 315
and 603 nmol/L for serum and 3.1% at 255 nmol/L for urine. Serum
leptin was measured by a commercial RIA (Linco Research, Inc., St. Louis, MO); the limit of detection was 0.5 ng/mL.
Serum estradiol was determined by RIA (Orion Diagnostica, Espoo,
Finland). Serum LH and FSH were determined by immunofluorometric assay
(Delfia, Wallac Oy), total T3 was determined by RIA
(Amerlex-M, Ortho Clinical Diagnostics, Amersham,
Aylesbury, UK), insulin was measured by double antibody RIA (Kabi
Pharmacia Diagnostics AB, Uppsala, Sweden), and plasma glucose was
determined by glucose dehydrogenase (Merck, Darmstadt, Germany).
Data analysis
The measured serum GH concentration profiles represent the combined outcome of GH secretion into and elimination from the blood. To uncover the secretory events, we evaluated the concentration time series by third generation, multiple parameter deconvolution analysis, which allows the convolution integral to be solved by considering secretion and clearance parameters as simultaneous unknowns. Data were analyzed blind. This has been described in detail by Veldhuis et al. (17, 18).
Regularity in GH and cortisol serum concentration-time series was quantified with a recently introduced statistic, termed ApEn, which quantify the logarithmic likelihood that patterns that are similar remain similar on the next incremental comparison. ApEn analysis is model independent (no assumptions about periodicity or waveforms) (22, 24). It detects differences in underlying episodic behavior not reflected simply in the mean or the variance of hormone concentrations or in peak occurrence or amplitudes (24). ApEn has been demonstrated to be stable to small changes in noise and infrequent data artifacts. The ApEn score generally increases with increasing process irregularity and increasing intraassay variation (24). In the present study, only datasets with similar assay CVs were compared. Two input parameters, m and r, must be fixed to compute ApEn. In choosing the r input parameter as a fixed percentage of each dataset’s SD, the regularity statistic is normalized, making ApEn scale independent. The ApEn application with m = 1 estimates the rate of entropy for a first order-approximating Markov chain to the underlying true process (22, 24). In the present study we calculated ApEn (r, m) for the GH datasets (r = 20% SD, m = 1) and for the less frequently sampled cortisol datasets (r = 80% SD, m = 1). Although absolute ApEn values typically vary considerably with m and r, it has previously been shown that relative contrasts are replicated with different in-out parameter choices, which confers robustness and necessary clinical validity (22). The rationale for choosing r = 20% SD was discussed by Pincus et al. (25). The role of conditioned probabilities is explained in the same paper (25). We used the same m and r input parameters, which have been used in other hormone time-series studies performed to date. Thus, there has been no "parameter fiddling" in an attempt to find m, r pairs to substantiate a test hypothesis. Twenty-four-hour circadian variations in serum GH concentrations were analyzed using nonlinear, unweighted, least squares cosine approximations (cosinor analysis). The mesor (mean value about which the oscillations occur), cosine amplitude (half the difference between the highest and lowest values), and acrophase (time of maximal concentration) were calculated.
Results are expressed as group mean values (±SEM), and comparisons between groups were performed by Mann-Whitney test (except in the paired weight gain study, where the Wilcoxon test was used). Bivariate correlations were estimated using Spearman coefficients. The areas under hormone profiles (AUC) were calculated by the trapezoidal rule. P < 0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Figure 1 shows representative
examples of the 24-h serum GH concentration profile (discrete data
points in the upper panels), the corresponding
deconvolution-resolved secretion profiles (lower panels),
and the calculated (reconvolved) curves (continuous curves in
upper panels). The reconvolved continuous curves
depict the serum GH concentration profiles predicted when GH secretory
events occur as estimated in the lower left panels. These
fitted curves allow the investigator to visualize how well the model
describes the actual measured serum GH concentrations, thereby
providing a check on the reasonableness of the estimated parameters.
The predicted convolution curves closely approximate the measured GH
concentrations of the subjects. Similar close approximations were
obtained for all 23 serial datasets in the present study.
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. The
estimated half-life of endogenous GH was unchanged in AN. Deconvolution
analysis revealed that pituitary secretory GH burst frequency was
significantly increased in AN (P < 10-4),
and interburst intervals were reciprocally reduced (P
< 10-4). GH secretory burst amplitudes were
nonsignificantly increased in the anorectic patients (P
= 0.13), whereas the mass as well as the duration of the bursts (the
duration at half-maximal amplitude) were significantly increased
(P < 0.05). The 24-h mean GH concentrations and the
24-h integrated concentrations were 10-fold increased in AN. The basal
secretion rates as well as the pulsatile secretion rates were increased
in the anorectic group (P < 0.05; Fig. 2). The percentage of GH secreted in a
pulsatile manner tended to be reduced in AN patients (P
= 0.058).
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).
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, the ApEn (1,
20% SD) values were significantly higher in the patients
with AN compared to the controls (1.03 ± 0.07 vs.
0.61 ± 0.07; P < 0.01).
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,
which indicate 30- and 45-fold increases in amplitude and mesor,
respectively. There was no significant difference in the occurrence of
acrophase; however, it seemed to be more dispersed in the AN
patients.
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Cortisol
Cortisol was measured in duplicate at 1-h intervals over
24 h. As shown in Table 1
, the 24-h mean serum concentrations of
cortisol and the 24-h urinary cortisol excretion rates were
significantly elevated in the AN patients compared to the controls. In
the whole study group, the cortisol levels were negatively correlated
to BMI (24-h mean serum cortisol vs. BMI: r = -0.71,
P < 0.01; 24-h urinary cortisol excretion
vs. BMI: r = -0.58, P < 0.01).
Moreover, the cortisol levels were positively correlated to basal as
well as pulsatile GH secretion and to the GH burst frequency, but not
to GH burst mass (24-h basal GH production vs. 24-h mean
serum cortisol: r = 0.52, P < 0.05; 24-h
pulsatile GH secretion vs. 24-h mean serum cortisol level:
r = 0.48, P < 0.05; secretory GH burst frequency
vs. 24-h mean cortisol level: r = 0.53,
P < 0.05; secretory GH burst mass: r = 0.40,
P = 0.09). Cosinor analysis of cortisol levels
disclosed that the cosine mesor was significantly increased (477
± 67 vs. 251 ± 17 mU/L; P < 0.01),
whereas the diurnal rhythm was preserved in the anorectics, with no
difference in amplitude (134 ± 18 vs. 117 ± 12
mU/L; P > 0.05) or acrophase (1246 ± 23
vs. 1253 ± 23 min; P > 0.05). After
weight gain, cortisol levels did not change significantly (mean 24-h
serum concentration fell from 414 ± 47 to 344 ± 25 nmol/L
and 24-h urinary excretion rate declined from 381 ± 66 to
300 ± 55 nmol/24 h).
Other hormones
Fasting serum concentrations of IGF-I, IGFBP-1,
IGFBP-3, leptin, LH, FSH, estradiol, total T3, insulin, and
plasma glucose in AN patients and controls are listed in Table 1. There
were significant decreases in IGF-I and IGFBP-3 levels, and IGFBP-1
levels were increased in the AN patients. Leptin, LH, FSH, estradiol,
total T3, and insulin levels were significantly decreased
in AN patients, whereas there were no difference in fasting glucose
levels. There were no significant correlations between IGF-I and GH
levels. In the whole study group (n = 19) leptin levels were
inversely correlated to the pulsatile (r = -0.60;
P < 0.01), but not the basal (r = -0.35;
P = 0.14), GH secretion rate.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The observed elevation in nonpulsatile GH secretion in AN probably indicates a reduced hypothalamic SRIH tone, whereas the increase in GH pulse frequency could indicate an increased frequency of hypothalamic GHRH discharges. Basal as well as pulsatile GH secretion rates were significantly correlated to BMI, suggesting that the reduced SRIH tone as well as the increased GHRH secretion are related to the weight loss (or a covariate) in AN. This hypothesis is consistence with the observation that all pulsatile values upon weight gain changed in the direction toward the controls, although statistical significance could not be attained in the small sample size.
Recently, 24-h deconvolved GH pulsatility was studied in normal weight women with hypothalamic amenorrhea (20). As the participating subjects in that study showed significant psychological abnormalities characteristic of eating disorders (20), this could be a reasonable model to study the confounding impact of hypoestrogenism vs. weight loss in AN. In these hypothalamic amenorrheic women, the 24-h mean GH levels did not differ from those in weight-matched controls; however, basal GH secretion was increased 2-fold, whereas the pulsatile GH secretion was 40% lower than the control value (20), and interestingly, the pulse frequency was increased, whereas the amplitude was blunted (20). Unfortunately, ApEn was not reported (20). On the basis of these observations, we hypothesize that the pathogenesis of augmented pulsatile GH secretion in AN is caused by two distinct mechanism; one related to the weight loss preferably increasing burst mass, and one related to hypoestrogenism preferably increasing pulse frequency.
Using ApEn analysis to evaluate the serial regularity of GH secretion in AN, we found that patients with AN exhibit significantly greater ApEn values in GH concentration time series than controls. This analysis has not previously been applied to patients with AN or to other forms of chronic malnutrition. However, in normal weight healthy subjects, the ApEn increased after overnight fasting in 10 males, but not in 6 females (21). This possible gender difference in the GH response to fasting has not yet been confirmed. However, females have higher ApEn values than males (22), suggesting that sex steroids could be involved in the control of secretory GH orderliness, which strongly reflects within-axis feedback control (23).
On the basis of mathematical networks analysis, it has been demonstrated that ApEn increases with greater system coupling and greater external influences (24). In line with this perspective, the present data suggest an altered and more complex neuroendocrine regulation of GH secretion in AN. This may be caused by an increased number and/or intensity of control factors interacting with hypothalamic GHRH and SRIH release. However, to specify the sources of the input variability determining GH secretory irregularity in AN, further experimental studies are needed.
GH half-life has previously been found to be inversely correlated to BMI (26, 27) and possibly to the serum estradiol level (28) at least in normal weight and obese subjects, suggesting that a prolonged GH half-life could be a factor contributing to the hypersomatotropic state in AN. However, as we demonstrate here no significant differences between the groups in mean half-life of GH disappearance resolved by deconvolution analysis, the present study does not support this hypothesis. To our knowledge, GH half-life has not previously been determined in AN or other forms of emaciation without liver and renal diseases. In normal subjects, GH half-life was not altered by fasting (29).
The diurnal GH secretory pattern was evaluated by 24-h cosinor analysis. In the AN patients, mesor and amplitude were increased, whereas there was no difference in acrophase rhythm. The latter finding does not support the hypothesis that time-dependent hypothalamic signals are disturbed in AN. GH cosinor analysis in AN patients has only been performed once before in the literature, collecting blood at 4-h intervals, and this study also did not show a significantly altered GH acrophase (30).
Confirming earlier studies (8, 31, 32), we found low circulating total IGF-I levels, presumedly resulting in diminished feedback inhibition of GH secretion. However, there were no significantly inverse correlations between IGF-I and GH levels. There are conflicting reports on the level of free IGF-I in AN (32, 33), and it is not known to what extent free IGF-I serum concentrations reflect IGF-I tissue levels. In the AN patients, significant elevated 24-h mean serum cortisol concentrations and urinary free cortisol excretion were found. In contrast to Cushingoid hypercortisolemia (34), the secretory orderliness of cortisol was intact in AN. These observations suggest that hypercortisolemia in AN might be caused by an altered set-point of CRH-ACTH secretion, rather than an essentially perturbed neuroendocrine regulation. It is well established that long term high dose glucocorticoid treatment in children leads to growth failure, and there is evidence that cortisol interferes with the somatotropic axis at various levels (35, 36). At the central level, chronic administration of glucocorticoids leads to suppression of stimulated (37) and spontaneous GH secretion (38). Deconvolution analyses have shown that GH secretion suppressed by high doses glucocorticoid resulted from a reduced burst mass, rather than reduced secretory burst frequency (38, 39). If an inhibitory effect of cortisol on GH secretion played a significant role in AN, one should expect the cortisol level to be negatively correlated to the 24-h GH secretion rate and especially to the secretory GH burst mass. This relation was, in fact, reported in a study of 5 days of fasting in healthy subjects (39). In contrast in the present study, there was a positive correlation between cortisol levels and 24-h GH secretion levels or GH burst mass. Accordingly, we hypothesized that firstly, the interaction between these two axes in acute starvation is altered compared with that in the chronically emaciated state of AN, and, secondly, the hypercortisolemia in AN does not essentially suppress the central regulation of GH secretion in AN.
In normal weight subjects, an inverse correlation between serum levels of GH and leptin has been reported (40) and could reflect the lipolytic effect of GH on body fat percentage (41). In addition, there is evidence that leptin via hypothalamic receptors influences GH release in the rat, and it has been hypothesized that the impairment of GH secretion observed in obese subjects is due to the high leptin level associated with obesity (42). In continuation of this idea, it is tempting to speculate that low leptin levels could be involved in the GH hypersecretion in patients with AN. The present data disclose that leptin is significantly inversely correlated to the pulsatile, but not the basal, GH secretion rate, which indirectly could indicate that leptin is involved in regulation of GHRH release. However, to date the potential influence of leptin on GH secretion in the human remains speculative, as experimental data are still scanty (43). In fact, swine and rodent studies have demonstrated a stimulatory, rather than a suppressive, effect of leptin on GH release (44, 45). However, the rodent and human GH-IGF-I axes show opposite responses to nutritional interventions (36).
In conclusion, the present deconvolution and entropy data suggest that enhanced GH secretion in AN is due to markedly altered neuroendocrine regulation of GH axis dynamics, resulting in jointly increased hypothalamic GHRH discharges and reduced hypothalamic somatostatinergic tone.
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Acknowledgments |
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Footnotes |
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Received December 3, 1998.
Revised February 17, 1999.
Accepted February 26, 1999.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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) and in women with AN (
). *, P <
0.05 (AN vs. controls).
), women with AN
(
), and women with AN after weight gain
( 
). Basal GH
secretion vs. BMI: r = -0.56, P < 0.05;
pulsatile GH secretion vs. BMI: r = -0.61,
P < 0.01 (Spearman coefficients).
) and in women with AN (