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Clinical Studies |
Department of Pediatrics, Autonomous University, Division of Pediatric Endocrinology (J.A., N.C., V.B., M.T.M., J.P., M.H.) and the Division of Pediatric Psychiatry (G.M.), Hospital of Niño Jesús,E-28009 Madrid; and the Laboratory of Molecular and Cellular Neuroendocrinology, Ramón y Cajal Institute, Madrid, Spain
Address all correspondence and requests for reprints to: Jesús Argente, M.D., Ph.D., Division of Pediatric Endocrinology, Department of Pediatrics, Hospital Niño Jesús, Avenida Menéndez Pelayo 65, 28009 Madrid, Spain.
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Abstract |
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In conclusion, the GH-IGF axis is dramatically altered in patients with anorexia nervosa. Changes in the peripheral IGF system, however, appear to be independent of modifications in GH secretion and, in contrast to current thought, not all of the observed abnormalities are rapidly reversed with weight recuperation.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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6%) (3)
and is the third most frequent cause of chronic disease in adolescent
girls (4). Although the true prevalence of the disease is not well
established internationally, most researchers agree that anorexia
nervosa has increased at least 5-fold during the last 30 yr in western
industrialized countries (5). In fact, this disease may be present in
1% of upper class adolescent girls in the United Kingdom (6) and 2.9%
of South African schoolgirls (7). One study performed among adolescents
in the area of the community of Madrid, Spain, between 1985 and 1987
showed that the prevalence of anorexia nervosa was 0.31% (8). Today,
most authorities estimate the prevalence around 1% in white females,
although subclinical disease could include up to 5% of the population
(9). The world incidence of new cases per year is around 1/100,000
inhabitants, and the prevalence may be even higher among certain high
risk groups, such as ballet dancers, gymnasts, and athletes (10). Much interest has focused on the endocrine abnormalities in patients with anorexia nervosa, which include amenorrhea, hypercortisolism, and hypothyroidism. In addition, because of the malnutrition seen in these patients, a number of studies have been reported in which GH levels were analyzed. Most researchers have shown increased GH levels in patients with anorexia, which return to normal after nutritional therapy (11); however, little is known regarding modifications of serum insulin-like growth factor I (IGF-I), its binding proteins (IGFBPs), or GH-binding protein (GHBP) levels at diagnosis and after nutritional and corporal recovery.
The aims of this study were 1) to determine serum GH, total IGF-I, free IGF-I (fIGF-I), IGF-II, insulin, IGFBP-1, IGFBP-2, IGFBP-3, and GHBP levels in patients with anorexia nervosa at diagnosis and compare these results with those for normal subjects of the same age, sex, and pubertal stage (12); 2) to investigate the changes in these parameters after weight recuperation; and 3) to analyze possible correlations between these parameters in anorexia nervosa.
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Subjects and Methods |
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The study population included 50 Spanish female adolescents (Tanner stage V) with anorexia nervosa and 56 healthy age- and sex-matched controls. All patients with anorexia nervosa met the DSM-IV criteria from the latest Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association (10).
The mean ages of the controls and patients with anorexia nervosa were 17.3 \ 0.4 and 16.12 \ 0.22 yr, respectively. Every patient consulted the Division of Endocrinology of our hospital after the diagnosis of anorexia nervosa was made at the Division of Psychiatry of the same hospital. All normal subjects were referred to the Division of Endocrinology for suspected endocrine abnormalities and were found to be normal, with a height between -1 and 1 SD according to Spanish standards (13).
GH studies
Spontaneous GH secretion was studied throughout a 24-h period in all anorexic patients and in 20 control subjects. At least 30 min before beginning the study, a venous catheter was placed in the right arm. Between 0800–0800 h, 1 mL blood was extracted every 30 min. The blood was immediately centrifuged, and the plasma was extracted and frozen until GH analysis was performed. During their hospitalization, patients were given a normal diet (breakfast, lunch, snack, and dinner) and water ad libitum and were allowed to move about normally. Lights were turned off from 2300–0700 h. The computerized mathematical algorithm Cluster (14) was used to determine GH secretion per 24 h, number of GH secretory burst per 24 h, maximum peak height of GH per 24 h, pulsatile area under the curve (PAGH), and total area under the curve. The integrated concentration of GH (ICGH) per 24 h was obtained by dividing the total area under the curve by 1440 (the duration of the study expressed in minutes).
For all other parameters, blood samples were obtained in the morning from fasting subjects. The body mass index (BMI) was calculated as weight (kilograms)/height (meters)2. The BMI SD score was based upon normative data from Spanish children (13). All normal subjects exhibited a BMI between -1 and 1 SD. All subjects were informed of the purpose of the study and gave consent, as required by the local human ethics committee.
Weight recuperation study
In addition to psychiatric therapy, patients with anorexia nervosa received nutritional treatment. They were studied at three different points: 1) diagnosis; 2) after recuperation of between 6–8% of the weight at diagnosis (84% of the patients; n = 42), sometime between 2 weeks and 2 months after beginning treatment; and 3) when 10% or more of the initial weight was recuperated (40% of the patients; n = 20), approximately 1 yr after diagnosis.
Biochemical measurements
Serum GH measurements were performed by RIA (Nichols Laboratories, San Juan Capistrano, CA). Total IGF-I was performed by RIA (Nichols Laboratories) after acid-ethanol extraction of serum. IGF-II, IGFBP-2, and free IGF-I (fIGF-I) were measured by RIA (Diagnostic Systems Laboratories, Webster, TX). Serum IGFBP-1 levels were determined by enzyme-linked immunosorbent assay (Medix Biochemica, Kauniainen, Finland) on nonextracted serum. IGFBP-3 was performed by RIA (Mediagnost, Tübingen, Germany). Intra- and interassay coefficients of variation were 4.2% and 7.2% for GH, 4.9% and 8.9% for IGF-I, 6.2% and 7.3% for fIGF-I, 5.2% and 8.7% for IGF-II, 4.6% and 9.8% for IGFBP-1, 5.7% and 7.2% for IGFBP-2, and 3.6% and 6.1% for IGFBP-3, respectively. Insulin was determined by RIA (Diagnostic Products Corp., Los Angeles, CA). The intra- and interassay coefficients of variations were 5.4% and 7.3%, respectively. GHBP assays were performed in duplicate by using a monoclonal antibody assay (Endocrine Sciences, Calabasas Hill, CA) that involves incubating patient serum with excess radiolabeled human GH and the monoclonal antibody MoAb 263, as previously described (12). The intra- and interassay coefficients of variation were 5.6% and 9.5%, respectively.
Statistics
All data are reported as the mean \ SEM. Because only a subpopulation of patients achieved the required levels of weight recuperation during the study period, statistical analyses to determine changes with weight recuperation were performed with a one-way ANOVA with repeated measures, using only those patients who reached the recuperation criteria. The baseline values of each subgroup were also calculated, and analysis was performed to determine whether this differed between the subpopulations. No significant differences were found between these subpopulations in the baseline levels of any parameter, and results are represented graphically using all data in each group. When only two experimental groups were compared, Student’s t test was applied. For more than two experimental groups, analysis was performed by a one-way ANOVA or ANOVA with repeated measures, followed by Scheffe’s F test. Correlations were performed using simple regression analysis. P < 0.05 was chosen as the level of significance.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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.
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). Although patients in group I had a
significant decrease in their PAGH and ICGH after weight recuperation
(P < 0.01), patients in group II had increases in both
parameters (P < 0.01; Fig. 1). After recuperation of
6–8% of their initial weight, PAGH and ICGH returned to normal in
both groups.
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. As can be seen,
there were no significant differences between these two groups.
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). Therefore, the results reported in the graphs and
regression analyses represent all anorexic patients. As shown in Fig. 2A, total serum IGF-I levels were decreased
significantly in patients with anorexia nervosa at diagnosis and did
not change significantly even after recuperation of 10% or more of
their initial weight (by ANOVA, P < 0.01). At
diagnosis, fIGF-I levels (Fig. 2B) were higher than control values;
they increased significantly after recuperation of 6–8% of the
initial weight and even further as more weight was gained (by ANOVA,
P < 0.01). A similar phenomenon was seen with serum
IGF-II levels (by ANOVA, P < 0.05; Fig. 2C). Insulin
levels were decreased significantly at diagnosis, fell significantly
lower after recuperation of 6–8% of the initial weight (by ANOVA,
P < 0.01), and remained low 1 yr after treatment began
and 10% or more of the initial weight was regained (Fig. 2D).
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) and IGFBP-2 (Fig. 3B) levels
were significantly elevated in anorexic patients at diagnosis. After
recuperation of between 6–8% of body weight, serum IGFBP-2
levels decreased significantly (by ANOVA, P < 0.001).
IGFBP-1 levels decreased after recovery of more than 10% of the
initial weight, but both IGFBP-1 and IGFBP-2 levels remained
significantly higher than control values.
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; by ANOVA, P
< 0.001).
As shown in Fig. 3D, anorexia patients had significantly decreased
serum GHBP levels (by ANOVA, P < 0.001) at diagnosis,
and a significant increase was seen with weight recuperation, with
values returning to normal after at least 10% of the initial weight
was gained (by ANOVA, P < 0.001).
Regression analyses
The results of all regression analyses performed are represented
in Table 4. No correlation was seen between BMI
(expressed as the SD) and GHBP in anorexic patients at
diagnosis or after weight recuperation (Fig. 4A),
whereas in controls this relationship was significant (Table 4). A
significant positive correlation was found between the BMI and serum
fIGF-I (Fig. 4B) only after weight recuperation. Similarly, the
correlations between BMI and levels of IGFBP-1 and IGFBP-2 were
significant only after recuperation of at least 10% of the initial
body weight. No correlation was found between BMI and serum IGFBP-3,
IGF-II, IGF-I plus IGF-II, or insulin levels at any time (Table 4).
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). IGF-II and IGF-I plus IGF-II correlated significantly
with serum IGFBP-2 only at the time of diagnosis. The sum of IGF-I plus
IGF-II (Fig. 4D) and IGF-II correlated positively with serum IGFBP-3 at
all points of the study. No correlation was found between serum GHBP
levels and IGF-I, fIGF-I, IGF-II, or IGF-I plus IGF-II in the anorexia
nervosa patients or the controls (Table 4). Ratios of IGFBP-2/IGF-I and IGFBP-2/fIGF-I
The ratio of IGFBP-2 to IGF-I has been proposed as a parameter to aid in differentiating between GH deficiency and malnutrition syndromes. At the time of diagnosis, patients with anorexia nervosa exhibited a significantly higher IGFBP-2/IGF-I ratio (4.12 \ 2.5) than controls (0.35 \ 0.04; P < 0.0001). This ratio declined, but remained significantly elevated even after recuperation of 6–8% (0.82 \ 0.1; P < 0.0001) or 10% or more of the initial weight (1.21 \ 0.3; P < 0.0001). In contrast, although these patients had a significantly elevated IGFBP-2/fIGF-I ratio at diagnosis (1311 \ 423 vs. 397 \ 96; P < 0.001), no differences were seen after weight recovery compared to control values (432 \ 93 and 397 \ 96, respectively).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Because anorexia nervosa is a form of malnutrition, GH secretion has been analyzed frequently in these patients; however, there are few studies that include measurements of GH secretion and the peripheral GH-IGF system both at the time of diagnosis and after weight recuperation. It has been reported that fasting enhances GH secretion in normal subjects (15). Patients with anorexia nervosa, however, may exhibit low GH levels at the onset of the disease (16). Golden et al. (16) postulated that if energy deprivation is maintained, these patients may develop GH resistance, leading to a rise in GH. Some researchers suggest that a negative relationship exists between weight or BMI and GH secretion (11, 17, 18).
Our findings are not in agreement with any of these theories. We did not find a correlation between GH secretion and the duration of the disease, weight, or BMI. In addition, we suggest that there are two distinct populations regarding the GH secretory pattern, i.e. normal to hypersecretors and hyposecretors. Both the PAGH and the ICGH per 24 h were increased in the hypersecretory group and decreased in the hyposecretory group. After recuperation of only 6–8% of the initial weight, both parameters in both groups returned to control values, suggesting that normal spontaneous GH secretion rapidly recuperates with nutritional therapy, as has been demonstrated previously (11, 19). As there was no difference in the number of GH secretory bursts between either pathological group and the control population, the abnormalities in the spontaneous GH pattern are most likely due to modulation of the amplitude of the secretory episodes and not their frequency. Although the explanation for this phenomenon remains unclear, we hypothesize that because anorexia nervosa is a heterogeneous disease in regard to its etiology and involved psychiatry, changes occurring in the central nervous system may also be heterogeneous, resulting in diverse neuroendocrine outputs. Regardless of the explanation, our data provide evidence that GH secretion in patients with anorexia nervosa is heterogeneous.
We postulate that the changes observed here in the peripheral GH-IGF axis are controlled mainly by nutrition and not by GH. We recently demonstrated that children with insulin-dependent diabetes mellitus show a partial GH resistance syndrome (20). These patients, with good nutrition but hypoinsulinemic due to the destruction of pancreatic ß-cells, have significantly decreased IGF-I and GHBP levels, but normal IGFBP-3 levels, whereas GH levels tend to be high. In contrast, patients with anorexia, who are hypoinsulinemic due to malnutrition, show complete alteration of the peripheral GH-IGF system, with reduced IGF-I, GHBP, and IGFBP-3; increased IGFBP-1 and IGFBP-2; and either high or low GH secretion. Obese patients, who, in contrast to those with anorexia nervosa, are hyperinsulinemic and overnourished, also show a generalized modulation of the peripheral GH-IGF axis (see accompanying manuscript). Although many of the changes are opposite in these two nutritional disorders, others are similar, such as significant increases in IGF-II and fIGF-I, and decreased GH secretion in all obese and some anorexia patients. Together, these data suggest that although both nutrition and GH secretion play important roles in the direct regulation of the peripheral GH-IGF axis in these conditions, other factors must also be involved.
Total serum IGF-I has been reported to be low in patients with anorexia nervosa (11, 17, 21, 22, 23). Our data showing a 200% reduction in total IGF-I levels are in agreement. Interestingly, we saw no difference in IGF-I levels between GH hyper- or hyposecretors, suggesting that this reduction is related to the state of malnutrition and not to GH levels. After weight recuperation, even though GH secretion returned to normal, IGF-I levels did not change significantly. It may be that more time is required, as we have observed that in other types of malnutrition, such as coeliac disease, at least 2 yr are necessary to normalize the decrease in IGF-I concentrations (24).
fIGF-I levels were normal at diagnosis, suggesting that the diminution of total IGF-I is due to a decrease in the bound IGF-I fraction. If fIGF-I is the biologically active fraction of this factor, these women, although having low overall IGF-I levels, may not be deficient in biologically active IGF-I. As IGFBP-3 is the main transporter of IGF-I in serum, the higher percentage of fIGF-I may be related to the significant reduction in this binding protein. Furthermore, the increase in fIGF-I as nutritional recuperation begins could be due to IGFBP-3 remaining low and IGFBP-1 and -2 declining, which would shift the proportion of IGF-I even further toward the free fraction.
At diagnosis, serum IGF-II levels in anorexic patients did not differ from those in the control population; however, there was a significant increase when weight recuperation started. Our basal data are in agreement with the report by Davenport et al. (25), but not with that by Counts and colleagues (11). However, similar to Counts et al. (11), we found a significant increase in IGF-II levels with nutritional therapy.
We confirm previous data showing markedly decreased GHBP levels in patients with anorexia nervosa (11, 17). In contrast to what was seen in the controls and in other studies of normal (12) and obese subjects (see accompanying manuscript), there was no correlation between serum GHBP levels and the BMI of anorexic patients. The low level of GHBP may be due to down-regulation of the number of GH cell surface receptors by the state of undernutrition or to a change in the enzymatic cleavage of the receptor to generate GHBP. Counts et al. (11) also suggest the possibility of an alteration in a separate, nutritionally regulated pathway to produce changes in the production or activity of GHBP. It is clear that this eating disorder leads to a decrease in the number and/or function of GH receptors, and this is independent of GH levels. This could help to explain at least in part why adolescents with anorexia nervosa have low levels of IGF-I and IGFBP-3, two GH-dependent proteins, even when GH secretion is elevated in a subpopulation of these patients.
Serum IGFBP-1 and IGFBP-2, both thought to be GH independent, although this may depend on the physiological state (26), were increased approximately 200% and 250%, respectively, compared to control values. These adolescents were extremely hypoinsulinemic at all stages of the study, which could partially explain the continued elevation of IGFBP-1 and IGFBP-2 levels even after weight recuperation. Serum IGFBP-1 and IGFBP-2 levels correlated inversely with insulin concentrations, as demonstrated previously (27), as well as with IGF-I, fIGF-I, IGF-II, and the sum of IGF-I and IGF-II. However, many of these correlations were significant only at the time of diagnosis. Although the biological functions of IGFBP-2 are not well understood, this factor is highly negatively correlated with fIGF-I and IGF-II at the time of diagnosis, suggesting that it may play an important role in modulating serum levels of these factors, at least in this model of undernutriton.
IGFBP-2 levels may be a good biochemical marker in growth and nutritional disorders during childhood because its concentrations are stable throughout the day and night and are not modified by nutrient ingestion. It has been suggested that the differential regulation of IGFBP-2 by GH and IGF-I could help to differentiate children with low IGFBP-3 and IGF-I serum levels as a result of inadequate nutrition from those who have GH deficiency. The data reported here suggest that the IGFBP-2/fIGF-I ratio may be an even better predictor of the state of nutrition. During malnutrition, the IGFBP-2/IGFBP-3 ratio is in the normal range, in contrast to what is seen in patients with GH deficiency, in whom it is significantly elevated. Furthermore, fIGF-I appears to be better than total IGF-I in predicting malnutrition, because as nutrition improves, the amount of fIGF-I increases significantly, whereas total IGF-I does not change. The same phenomenon is seen in obese patients (see accompanying manuscript). IGFBP-2 appears to be highly sensitive to metabolic disorders, with levels changing not only in the circulation, but also in other organs, as we demonstrated recently that both IGFBP-2 protein and messenger ribonucleic acid levels are modified in the cerebellum of diabetic animals (28).
The GH-dependent binding protein, IGFBP-3, was found to correlate with the sum of IGF-I and IGF-II in anorexia patients and controls and as seen previously in normal patients (12). There is also a correlation with total IGF-I, fIGF-I, and IGF-II. In contrast, we found no correlation between IGFBP-3 levels and the BMI SD score of anorexia patients or controls reported here or in obese patients (see accompanying manuscript), which is not in agreement with others (11). The reason for this discrepancy is not clear.
In summary, this paper demonstrates that patients with anorexia nervosa are not homogeneous in their pattern of GH secretion. This abnormality is an epiphenomenon of the disease, as nutritional recuperation restores it to normal, although the patients continue with the psychiatric problems associated with anorexia nervosa. The peripheral GH-IGF axis, however, is altered similarly in all patients, indicating that this is not totally dependent on GH secretion. Although serum insulin and total IGF-I levels are profoundly diminished, fIGF-I and IGF-II levels are in the normal range. In addition, all of the IGFBPs studied as well as GHBP are modified. Although after nutritional therapy these patients are no longer undernourished, and many have obtained a normal BMI, some of the parameters reported here as well as other biochemical markers, such as leptin (29), and physiological functions, such as the menstrual cycle, remain abnormal. Hence, it is clear that there is tight control over the physiological functions of the body in cases of undernutrition, and recuperation of these functions is not immediately restored when nutrition improves.
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Footnotes |
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Received October 28, 1996.
Revised December 11, 1997.
Revised January 24, 1997.
Accepted March 25, 1997.
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References |
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R. K. Støving, A. Flyvbjerg, J. Frystyk, S. Fisker, J. Hangaard, M. Hansen-Nord, and C. Hagen Low Serum Levels of Free and Total Insulin-Like Growth Factor I (IGF-I) in Patients with Anorexia Nervosa Are Not Associated with Increased IGF-Binding Protein-3 Proteolysis J. Clin. Endocrinol. Metab., April 1, 1999; 84(4): 1346 - 1350. [Abstract] [Full Text]
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G. A. Laughlin, C. E. Dominguez, and S. S. C. Yen Nutritional and Endocrine-Metabolic Aberrations in Women with Functional Hypothalamic Amenorrhea J. Clin. Endocrinol. Metab., January 1, 1998; 83(1): 25 - 32. [Abstract] [Full Text]
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, patients with anorexia nervosa
after recuperation of 6–8% of their initial weights; 
, patients
with anorexia nervosa after recuperation of 10% or more of their
initial weights.