Abstract

Objective: The aim of the current study was to analyze the relationships between plasma hormones, body weight parameters and stressful life events in anorexia nervosa (AN).Material and Methods: 72 females in the active phase of AN were evaluated. 52 healthy women constituted the control group. RIA kits were used to measure plasma hormone levels.Results: The concentrations of leptin, insulin, IGF-1, triiodothyronine, LH, FSH, estradiol, and testosterone were significantly lower and those of cortisol and growth hormone significantly higher in the AN than the control group. No hormonal differences between restrictive and binge-purging AN subtypes were found. Leptin, IGF-1, gonadotropins, and sex steroids correlated significantly negatively and growth hormone positively with total reduction of body weight or the degree of undernutrition. Associations were also found between lower insulin concentration and family violence, lower cortisol and psychiatric diseases in the family, higher testosterone and patient’s alcohol or drug abuse.Discussion: The changed activity of the somatotropin-somatomedin, gonadal, and corticotrophin axes corresponds to the clinical stage of AN. Plasma IGF-1 seems to be the most sensitive and useful independent hormonal marker of cachexia.

Introduction

It is still uncertain whether the psychiatric and/or endocrinal disturbances in anorexia nervosa (AN) are the results of a primary hypothalamic disorder or are indicative of longstanding malnutrition [5,51]. Body weight appears to be a crucial determinant of such dysregulation [5,11]. Puberty may itself be a risk factor of AN onset, which is why this disease most commonly develops during adolescence or young adulthood [28]. The European Symptom Checklist For Mental Disorders (ICD–10) describes disturbances of multiple hormonal axes in anorexia [24]. Amenorrhea is one of the main AN diagnostic criteria, which also include disturbed body image, fear of obesity, and aiming at minimal weight even when significantly underweight [1,24]. The American Psychiatric Association (DSM-IV) distinguishes the restricting subtype where low weight is maintained largely by caloric restriction and the bingeing/purging subtype with both binge eating and purging by vomiting, use of laxatives, diuretics, enemas and exercise [1]. Hypoleptinemia is believed to be the major signal underlying both somatic and behavioral adaptation to starvation [37]. Leptin, an adipose tissue- -derived adipocytokine, contributes to mechanisms responsible for body weight and energy balance regulation [19,54]. Receptors for leptin have been found in the brain and peripheral glands and it acts as a negative-feedback signal [15]. A certain threshold of leptin is necessary to activate the hypothalamic-pituitary-gonadal and thyroid axes, whereas the hypothalamic-pituitary-adrenal and growth hormone (GH)-insulin-like growth factor 1 (IGF- 1) axes may be largely independent of circulating leptin levels in humans [6,35,38]. On the other hand, hypoleptinemia may be subsequent to the decreased nutritional state and predicts secretion of estradiol, thyroid hormones, cortisol, and GH [35]. The role of leptin in abnormal eating behavior is unclear [38].

The recent literature focuses on the possible role of the hormones, severe life events and chronic stress as factors capable of influencing the onset and the course of eating disorders [30]. These psychoendocrine associations might be important for multidisciplinary and complementary AN treatment. The aim of the current study was to explore the relationships between selected clinical features, environmental (familiar) stressors and plasma concentrations of a broad spectrum of hormones involved in psychoendocrine reaction to prolonged starvation in patients with an active stage of anorexia nervosa.

MaterialsAndMethods

Participants

The study group consisted of 72 females aged 20.7 ± 3.5 years, admitted to the inpatient and outpatient services of the Psychiatry and Endocrinology Departments of Pomeranian Medical University in Szczecin from 1997 to 2007. All the patients met the criteria for anorexia nervosa of the Diagnostic and Statistical Manual for Mental Disorders, 4th ed., rev. (DSM-IV) [1], and the International Classification of Mental Disorders and Behavioral Disturbances, 10th ed., rev. (ICD-10) [24]. Forty-nine patients had the restrictive type of anorexia (AN-R) and 23 were bulimic (AN-B). Before blood sampling, all the participants were evaluated by a semi-structured clinical interview (SCID) for current or prior psychiatric illnesses suffered either by them or their first-degree relatives and their environmental situation (negative life events in patient’s life up to the moment of gathering data), alcohol or other substance abuse, and self-destructive behavior. The control group was composed of 52 healthy women who were mostly a representative group of medical students with an average age of 27.1 ± 6.3 years, with no history of an eating disorder or any substance abuse. None of the participants had received medication or hormonal therapy for a period of at least four weeks before the experiment. They were free of any somatic diseases such as primary endocrine, autoimmune, and gastrological disorders. Neurological processes that might cause central nervous system deficits were also excluded as well as pregnancy. All the participants received verbal and written information from the investigators about the purpose and design of the study. Informed consent to participate in this study was obtained from each participant and from the parents of the minors taking part in it. The experimental protocols were reviewed and approved by the Ethics Committee of the Pomeranian Medical University of Szczecin.

Hormone assays

Blood samples were collected in the early morning after an overnight fast and rest. In menstruating women a sample for hormonal measurements was collected in the folliculate phase (6-9th day of the cycle). Plasma was stored at -80ºC until assayed. Specific radioimmunoassay (RIA) kits were used to measure plasma levels of leptin (LEP) (Linco Research, Inc., St. Louis, MO, USA), cortisol (C) (Orion Diagnostica, Espoo, Finland), insulin-like growth factor 1 (IGF-1) (BioSource Europe S.A., Belgium), triiodothyronine and thyroxine (fT3 , fT4 ) (ZenTech, ANGLEUR Belgium), estradiol (E2 ) (BioSource Europe S.A., Nivelles, Belgium), and testosterone (T) (Orion Diagnostica, Espoo, Finland). Plasma insulin (IRI), thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), and luteotropic hormone (LH) were measured by immunoradiometric assay (IRMA) kits (BioSource Europe S.A., Nivelles, Belgium) and human growth hormone (GH) by immunoradiometric assay (GH-IRMA) kits (BioSource Europe S.A., Nivelles, Belgium). The sensitivities (the lower limits of detection) and intra- and interassay coefficients of variation were: 0.5 ng/mL, 3.4-8.3% and 3.0-6.2% for LEP; 5 nmol/L, 2.6-5.4% and 6.5-7.3% for C; 0.4 μg/L, 3.9-9.5% and 5-8% for IGF-1; 1.7 pmol/L, 3.6-4.2% and 3.4-4.8% for fT4 ; 17.6 pmol/L, 5.3-5.8% and 6.8-9.5% for E2 ; 0.1 nmol/L, 3.8-7.5% and 4.8-7.0% for T; 1 mIU/L, 1.6-2.2% and 6.1-6.5% for IRI; 0.025 mIU/L, 0.6-6.0% and 2.1-4.1% for TSH; 0.1 IU/L, 1.5-2.7% and 2.0-5.3% for FSH; 0.07 IU/L, 1.0-5.0% and 3.3-5.7% for LH; 0.026 mIU/L for GH, respectively.

Table 1. Clinical parameters of the anorexia (AN) group with division into restrictive (AN-R) and bulimic (AN-B) subtypes.

Nutritional status

Both the total time of illness (TTI, months) and total reduction of body weight (TRBW, kg) were determined. Some indices of body weight were also calculated, i.e. the body mass index (BMI) as the ratio of body weight [kg] to [height]2 and %IBW (percentage of ideal body weight) as the ratio of actual to ideal body weight (IBW) x 100%, where IBW (kg) = height (cm) – 100 – {[(height (cm) – 150)]/2} according to Lorentz’s formula [31].

Statistical analysis

The normality of distribution of quantitative variables was checked with the Shapiro-Wilk test. The statistical evaluation of differences between the groups was performed by means of Student t test for normally distributed variables or nonparametric Mann-Whitney test when the distributions were significantly different from normal. Associations between quantitative variables were characterized by Spearman’s rank correlation coefficient. The general linear model (GLM) was used for multivariate analysis. Statistica 7.1 software was used for statistical calculations. The results are presented as the mean ± SD (standard deviation) for normally distributed variables and as median (interquartile range) for non-normally distributed ones. The level of statistical significance was set at p<0.05 and it was not corrected for multiple testing.

Results

There was no significant association between the degree of undernutrition (TRBW, %IBW) and the type of anorexia, but BMI was lower in the restrictive type (Table 1).

The hormone concentrations in the AN-R and AN-B subgroups showed no significant differences (Table 2). Therefore we combined these subgroups and further analyses refer to the whole anorectic group. The anorectic and control groups were significantly different with regard to age, body weight (b.w.), and BMI (Table 3). The concentrations of LEP, IRI, IGF-1, fT3 , LH, FSH, E2 , and T were significantly lower and those of C and GH significantly higher in the AN group than in the controls (Table 3).

The associations of social factors and stressful life circumstances with clinical features and hormone concentrations in the patients with anorexia were explored and those with statistical significance are presented in Table 4. The patients with parental alcoholism were significantly older and had higher E2 and lower C values, while those who abused alcohol themselves had higher T concentrations. Drug abuse was associated with younger age and higher values of body weight, BMI, and T concentration. Patients with a history of parental separation or divorce had higher BMI. Lower concentrations of IRI were observed in patients with domestic violence, while the subgroup with psychological abuse had lower FSH. Patient’s competition with the mother was associated with a longer time of illness, while such behavior towards siblings correlated with significantly lower LH, FSH, and E2 concentrations. In patients with a history of psychiatric disease in the family, the concentration of cortisol was lower than in those free of this stressor.

Table 2. Hormonal characteristics of the anorexia nervosa patients stratified into restrictive (AN-R) and bulimic (AN-B) subtypes

Table 3. Characteristics of the anorexia nervosa (AN) and control (C) groups

Table 4. Clinical features and plasma hormone concentrations according to environmental stress events in AN patients

The correlations between clinical features and nutritional status parameters on the one hand and hormone concentrations on the other in the patients and controls are presented in Table 5. In the AN group the strongest associations concerned IGF-1, which correlated positively with body weight, %IBW, and BMI (Figure 1) and negatively with TRBW. Similar but much weaker associations were observed for leptin, LH, FSH, E2 , and T. fT4 correlated positively only with TTI. In contrast to the other hormones, GH had a negative correlation with %IBW and positive with TRBW. The correlations of IRI and TSH and fT3 with body weight parameters were not statistically significant.

In the controls, negative correlations between fT3 and body weight and BMI were found, while age correlated positively with E2 and negatively with IGF-1 and fT3 (Table 5). The other hormones did not significantly correlate with body weight parameters in this group. Correlation between plasma hormone concentrations in the AN patients are presented in Table 6. Multivariate analysis adjusted for patient age, total time of illness, and type of anorexia (restrictive or binge-purging) revealed that high IGF-1 concentration was a strong independent predictor of higher BMI, %IBW, and lower TRBW (Table 7).

Discussion

Multiple endocrine and metabolic changes are involved in the adaptation to survive prolonged starvation in the course of anorexia nervosa. To define these mechanisms it is necessary to sum the numerous pathways, as even minor weight changes in AN are associated with significant responses in basal and dynamic hormonal secretion [11,51]. As regards age and duration of illness in anorectic subgroups, no statistically significant differences were confirmed in our data, similarly to other authors [12], although the patients with bulimia had a slightly higher (by 0.9 kg/m2 ) BMI value. This difference could be explained by different principles and rituals pattern in AN-R and AN-B behavior according to anorexia diagnostic criteria. Patients with AN-B who have significantly higher BMI in comparison to AN-R are more prone to develop bulimia nervosa later [40].

Table 5. Spearman rank correlation coefficients for clinical features and plasma hormone concentrations in the AN patients and the control group

Fig. 1. Correlations of IGF-1 plasma concentration and BMI in the AN patients and controls. Linear regression lines and Spearman’s rank correlation coefficients (Rs) are presented for each group

Our observations show that AN-R and AN-B patients have similar hormonal profiles and these data may suggest that from the metabolic point of view they suffer from the same disease. We confirmed total leptin secretion being significantly lower, both in the restrictive and binge eating/purging AN subtypes, than in the normal-weight women [8,36,38]. A negative correlation between leptin and TRBW and a positive correlation between leptin and BMI were found in the AN patients in our study. Some authors observed no significant correlations between leptin, BMI, and body weight values in AN [42], while others assumed that the correlation between leptin and BMI was preserved independently of any specific pathology [13]. Serum leptin concentration corresponds to the true status of adipose stores and is supposed to be responsible for changes in the neuroendocrine system [8,39]. Leptin seems to be a link between the central neuropeptides and the hypothalamus–pituitary–peripheral hormones [48]. The central anorectic role of leptin is believed to inhibit the anabolic (orexigenic) pathway connected with such agents as AgRP (Agouti-related protein), NPY (neuropeptide Y), β-EP (β-endorphin), MCH (melanin-concentrating hormone), galanin, hypocretins (OXA, OXB), glutamate and NMDA [48]. On the other hand, leptin seems to stimulate a catabolic (anorexigenic) pathway of the central nervous system connected with CRH (corticotrophin-releasing hormone), TRH (thyrotropin-releasing hormone), POMC (proopiomelanocortin), α-MSH (α-melanocortin), CART (cocaine- and amphetamine-regulated transcript), and BDNF (brain-derived neurotrophic factor) [21,48,49]. TNFα could also contribute to the hormonal changes and to the loss of appetite due to interaction with leptin and NPY signaling [48]. Leptin with its receptor (LepRb) and the melanocortin system with MC4R signaling in neural and physiological pathways may be crucial for processes of nutritional regulation [45].

Table 6. Spearman rank correlation coefficients for plasma hormone concentrations in the AN patients

Table 7. Multiple linear regression analysis (GLM) of associations between body weight parameters and patients’ age, type of anorexia (restrictive or binge-purging), total time of illness, and IGF-1 plasma concentration

The cortisol level in the examined anorectic women were higher than in the controls. Our study confirmed the opinion that cortisol is usually elevated in anorexia [20,23,26,32,34,41]. According to some authors, hypercortisolemia is one of the most characteristic hormonal symptoms in AN [32,41]. Serum cortisol at low body weight is a significant predictor of visceral adipose tissue redistribution after weight gain [32]. On the basis of endocrinological observations, alteration of the CRH -ACTH-cortisol axis in AN is secondary to starvation [51]. Hypersecretion of CRH is a compensatory mechanism counteracting cortisol resistance in feedback regulation [23] which probably is involved in the vicious circle maintaining the emaciated state [51], while a reduced rate of cortisol breakdown might be responsible for energy conservation [10]. We did not confirm a previously reported inverse correlation between cortisol and BMI in AN patients [34,41]. We observed lower cortisol secretion in anorectic patients with psychiatric disease in the family. According to a pathophysiological model, severe stressors or increased plasma cortisol might trigger a host of harmful (brain or peripheral tissue) derangements [22]. This especially concerns individuals carrying a genetic risk for psychiatric disorders such as anorexia nervosa, alcoholism, and affective disorders [22,25]. In anorexia nervosa, neuropsychological deficits are usually linked to elevations in cortisol level, while the structural abnormalities in the brain are similar to those seen in schizophrenic patients [28] who are impaired in their biological response to stress by showing a blunted cortisol secretion to psychosocial stress [17]. Up to 90% of AN patients demonstrate depressive symptoms during the acute phase of illness [28].

The level of insulin was lower in the AN than in the control women. Such results are typical of chronic starvation [2]. No correlations between IRI and the clinical parameters were found except for the association of IRI and domestic violence. Some authors assume that women who have experienced parental physical and psychological abuse demonstrate more anorexic behavior [33,43]. However, complete suppression of appetite is doubtful because of the underlying volitional and, usually, egosyntonic resistance to eating drives [25]. On the other hand, proper parenthood with encouragement of child autonomy is associated with less dieting behavior, possibly serving a protective function against eating disorders [43]. Family violence is an extremely powerful trigger which may lead to activation of the glucose-insulin-cortisol-related pathways in autonomic response to psychological distress and requires further exploration.

IGF-1 was significantly lower and GH significantly higher in the AN group than in the controls and comparable in the AN-R and AN-B subgroups [11,50]. Adaptation to chronic starvation induces exaggerated GH and decreased IGF-1 secretion. Such changes are explained by disturbed control of hypothalamic GH release [46,47,50,51], peripheral GH resistance [47,51], and decreased levels of growth hormone-binding protein (GHBP) [30], leading to reduced IGF-1 synthesis [16] and impairment of the negative IGF-1 feedback action on GH release [16,52]. However, the peripheral IGF-1 system may be independent of any modifications in GH concentration [3], so that some anorectic patients may have diminished GH despite decreased IGF-1 secretion [18]. Our results support the notion that IGF-1 and GH are sensitive to chronic malnutrition [7] as these hormones significantly correlated with TRBW and %IBW. Following Stǿving et al., we demonstrated that IGF-1 plasma level showed the strongest correlations with each of the analyzed body weight parameters irrespective of the clinical subtype of illness [50]. These data are congruent with hypotheses that hormonal changes are secondary to nutritional deprivation [7,18,47] and that nutritional status may be a major determinant in the regulation of the somatotropin-somatomedin axis in humans [2,47]. Bioactivity of IGF-1 may be a suitable marker in emaciated patients with AN [50] as well as in other conditions of malnutrition and malabsorption [16]. On the other hand, these mechanisms connected with increased GH and decreased IGF-1 secretion appear to be protective of the self-destructive stress reaction called self-cannibalism [51], typically observed in long-lasting critical illness [46]. In this context, the positive correlation between IGF-1 and BMI in AN with a tendency to a negative correlation in the control group confirms a close relationship between IGF-1 secretion and nutrition state. In Figure 1 it can be observed that a BMI of 18.5 kg/m2 , which was arbitrarily determined as the boundary for anorexia nervosa diagnosis, is where the IGF-1 levels in the AN and control groups intersect. Thus plasma IGF-1 may be suggested as a sensitive hormonal marker of cachexia. It should be verified whether the level of 300 μg/L IGF-1, which corresponds to a BMI of 18.5 kg/m2 , might be of diagnostic value (Figure 1). Our results may support the hypothesis of Gianotti et al. [16] that the activity of the GH/IGF-1 axis in AN reflects only an impaired nutritional state and cannot be considered a primary hallmark of the disease.

Anorexia nervosa is usually associated with markedly decreased total and free T3 , normal or subnormal total and free T4 , and normal or lower TSH concentrations described as “low T3 syndrome” or “sick euthyroid syndrome” [27,44]. Our results are in agreement with this profile. The thyroid axis adapts its activity to weight status [44] and leptin is believed to be the link between body weight and TSH [38]. However, no correlation between TSH and body weight parameters was found previously [5] or in our AN patients. Such results may explain the adaptive mechanisms in AN responsible for cell energy expenditure.

Hypogonadotropic hypogonadism, a major diagnostic criterion of AN [41], is a final clinical effect of adaptive responses to pathological dieting and extreme undernutrition [9]. Our results confirm that serum gonadotropins and estradiol in AN (independent of subtype) are significantly decreased compared with the control group [32,50,53]. Our data showing that LH positively correlated with BMI [41,53], and FSH with duration of illness [53], are also in agreement with other reports. These changes are parallel to disturbances in the GHIGF-1 and corticotrophin axes described above [4,34] and decreased serum levels of leptin, IGF-1, and T3 , which are supposed to be nutritional markers of FHA (functional hypothalamus amenorrhea) [8,39]. Two metabolic determinants are important for primary or secondary amenorrhea. Low fat content in a range of 10-15% body weight is associated with cessation of menstrual cycles [14]. The second clinical determinant is leptin level – its serum concentration of 1.85 ng/mL is required to maintain menstruation [29].

In our study we observed positive associations of testosterone with alcohol and drug abuse in AN patients. Regarding the biological spectrum of testosterone, such observations could explain the proneness to impulsivity in anorexia. As individuals with the binge eating/purging subtype of AN are more often classified as likely to have histories of behavioral dyscontrol, substance abuse, and overt family conflict [25], the similar plasma levels of testosterone in both analyzed subgroups might show the better mechanisms of emotional control in AN-R than in AN-B patients.

A limitation of our study is significantly older age of females in the control group (Table 3). It was connected with ethical constraints in obtaining informed consent for examination of healthy adolescents. However, it is unlikely that the observed differences in hormone concentrations between groups were strongly influenced by an age difference equal to 5 years, and the main aim of our study was to explore the relationships within the anorexia group. Further research is needed to explain the role of many other neurotransmitters and inflammatory agents in AN and their interactions with genetic and environmental factors.

Conclusions

References

• 1. American Psychiatric Association Committee on Nomenclatureand Statistics. Diagnostic and statistical manual of mental disorders,4th ed. Washington D.C. American Psychiatric Association, 1994
  Google Scholar
• 2. Argente J., Caballo N., Barrios V., Muñoz M.T., Pozo J., ChowenJ.A., Hernández M.: Disturbances in the growth hormone-insulin–like growth factor axis in children and adolescents with differenteating disorders. Horm. Res., 1997; 48, Suppl.4: 16-18
  Google Scholar
• 3. Argente J., Caballo N., Barrios V., Muñoz M.T., Pozo J., ChowenJ.A., Morandé G., Hernández M.: Multiple endocrine abnormalities ofthe growth hormone and insulin-like growth factor axis in patientswith anorexia nervosa: effect of short- and long-term weight recuperation.J. Clin. Endocrinol. Metab., 1997; 82: 2084-2092
  Google Scholar
• 4. Audi L., Mantzoros C.S., Vidal-Puig A., Vargas D., Gussinye M.,Carrascosa A.: Leptin in relation to resumption of menses in womenwith anorexia nervosa. Mol. Psychiatry, 1998; 3: 544-547
  Google Scholar
• 5. Beumont P.J., George G.C., Pimstone B.L., Vinik A.I.: Body weightand the pituitary response to hypothalamic releasing hormones inpatients with anorexia nervosa. J. Clin. Endocrinol. Metab., 1976;43: 487-496
  Google Scholar
• 6. Blüher S., Mantzoros C.S.: The role of leptin in regulating neuroendocrinefunction in humans. J. Nutr., 2004; 134: 2469S-2474S
  Google Scholar
• 7. Caregaro L., Favaro A., Santonastaso P., Alberino F., Di Pascoli L.,Nardi M., Favaro S., Gatta A.: Insulin-like growth factor 1 (IGF-1), anutritional marker in patients with eating disorders. Clin. Nutr.,2001; 20: 251-257
  Google Scholar
• 8. Casanueva F.F., Dieguez C., Popovic V., Peino R., Considine R.V.,Caro J.F.: Serum immunoreactive leptin concentrations in patientswith anorexia nervosa before and after partial weight recovery. Biochem.Mol. Med., 1997; 60: 116-120
  Google Scholar
• 9. Chan J.L., Mantzoros C.S.: Role of leptin in energy-deprivationstates: normal human physiology and clinical implications for hypothalamicamenorrhoea and anorexia nervosa. Lancet, 2005; 366: 74-85
  Google Scholar
• 10. Couzinet B., Young J., Brailly S., LeBouc Y., Chanson P., SchaisonG.: Functional hypothalamic amenorrhoea: a partial and reversiblegonadotrophin deficiency of nutritional origin. Clin. Endocrinol.,1999; 50: 229-235
  Google Scholar
• 11. Douyon L., Schteingart D.E.: Effect of obesity and starvation onthyroid, growth hormone, and cortisol secretion. Endocrinol. Metab.Clin. North. Am., 2002; 31: 173-189
  Google Scholar
• 12. Favaro A., Ferrara S., Santonastaso P.: The spectrum of eatingdisorders in young women: a prevalence study in a general populationsample. Psychosom. Med., 2003; 65: 701-708
  Google Scholar
• 13. Ferron F., Considine R.V., Peino R., Lado I.G., Dieguez C., CasanuevaF.F.: Serum leptin concentrations in patients with anorexianervosa, bulimia nervosa and non-specific eating disorders correlatewith the body mass index but are independent of the respectivedisease. Clin. Endocrinol., 1997; 46: 289-293
  Google Scholar
• 14. Frisch R.E., McArthur J.W.: Menstrual cycles: fatness as a determinantof minimum weight for height necessary for their maintenanceor onset. Science, 1974; 185: 949-951
  Google Scholar
• 15. Frühbeck G., Jebb S.A., Prentice A.M.: Leptin: physiology andpathophysiology. Clin. Physiol., 1998; 18: 399-419
  Google Scholar
• 16. Gianotti L., Lanfranco F., Ramunni J., Destefanis S., Ghigo E.,Arvat E.: GH/IGF-1 axis in anorexia nervosa. Eat. Weight Disord.,2002; 7: 94-105
  Google Scholar
• 17. Gispen-de Wied C.C.: Stress in schizophrenia. Eur. J. Pharmacol.,2000; 405: 375-384
  Google Scholar
• 18. Golden N.H., Kreitzer P., Jacobson M.S., Chasalow F.I., SchebendachJ., Freedman S.M., Shenker I.R.: Disturbances in growth hormonesecretion and action in adolescents with anorexia nervosa. J.Pediatr., 1994; 125: 655-660
  Google Scholar
• 19. Haas V., Onur S., Paul T., Nutzinger D.O., Bosy-Westphal A., HauerM., Brabant G., Klein H., Müller M.J.: Leptin and body weight regulationin patients with anorexia nervosa before and during weightrecovery. Am. J. Clin. Nutr., 2005; 81: 889-896
  Google Scholar
• 20. Haas V.K., Kohn M.R., Clarke S.D., Allen J.R., Madden S., MüllerM.J., Gaskin K.J.: Body composition changes in female adolescentswith anorexia nervosa. Am. J. Clin. Nutr., 2009; 89: 1005-1010
  Google Scholar
• 21. Himmerich H., Schonknecht P., Heitmann S., Sheldrick A.J.: Laboratoryparameters and appetite regulators in patients with anorexianervosa. J. Psychiatr. Pract., 2010; 16: 82-92
  Google Scholar
• 22. Holsboer F., Spengler D., Heuser I.: The role of corticotrophin-releasinghormone in the pathogenesis of Cushing’s disease, anorexianervosa, alcoholism, affective disorders and dementia. Prog. Brain Res.,1992; 93: 385-413
  Google Scholar
• 23. Hotta M., Shibasaki T., Masuda A., Imaki T., Demura H., Ling N.,Shizume K.: The responses of plasma adrenocorticotropin and cortisolto corticotropin-releasing hormone (CRH) and cerebrospinal fluidimmunoreactive CRH in anorexia nervosa patients. J. Clin. Endocrinol.Metab., 1986; 62: 319-324
  Google Scholar
• 24. Janca A., Űstűn T.B., van Drimmelen J., Dittman V., Isaac M.: ICD– 10 Symptom Checklist For Mental Disorders Version 1.1, Hogrefe &Huber Publishers, World Health Organisation, Seattle-Toronto-BernGöttingen,1996
  Google Scholar
• 25. Kaye W.H., Klump K.L., Frank G.K., Strober M.: Anorexia and bulimianervosa. Annu. Rev. Med., 2000; 51: 299-313
  Google Scholar
• 26. Kennedy S.H., Brown G.M., McVey G., Garfinkel P.E.: Pineal andadrenal function before and after refeeding in anorexia nervosa. Biol.Psychiatry, 1991; 30: 216-224
  Google Scholar
• 27. Kiyohara K., Tamai H., Takaichi Y., Nakagawa T., Kumagai L.F.: Decreasedthyroidal triiodothyronine secretion in patients with anorexianervosa: influence of weight recovery. Am. J. Clin. Nutr., 1989; 50: 767-772
  Google Scholar
• 28. Klein D.A., Walsh B.T.: Eating disorders. Int. Rev. Psychiatry, 2003;15: 205-216
  Google Scholar
• 29. Kopp W., Blum W.F., von Prittwitz S., Ziegler A., Lübbert H., EmonsG., Herzog W., Herpertz S., Deter H.C., Remschmidt H., Hebebrand J.: Lowleptin levels predict amenorhhea in underweight and eating disorderedfemales. Mol. Psychiatry, 1997; 2: 335-340
  Google Scholar
• 30. Lo Sauro C., Ravaldi C., Cabras P.L., Faravelli C., Ricca V.: Stress,hypothalamic-pituitary-adrenal axis and eating disorders. Neuropsychobiology,2008; 57: 95-115
  Google Scholar
• 31. Lorentz F.H.: Ein neuer Konstitionsinde. Klin. Wochenschr., 1929;8: 348-351
  Google Scholar
• 32. Mayer.L, Walsh T.B., Pierson Jr. R.N., Heymsfield S.B., Gallagher D.,Wang J., Parides M.K., Leibel R.L., Warren M.P., Killory E., Glasofer D.:Body fat redistribution after weight gain in women with anorexia nervosa.Am. J. Clin. Nutr., 2005; 81: 1286-1291
  Google Scholar
• 33. Miskinyte A., Perminas A., Sinkariova L.: The relationship of eatingbehavior to body dissatisfaction and physical and psychological abusein childhood. Medicina (Kaunas), 2006; 42: 944-948
  Google Scholar
• 34. Misra M., Miller K.K., Almazan C., Ramaswamy K., Lapcharoensap W.,Worley M., Neubauer G., Herzog D.B., Klibanski A.: Alterations in cortisolsecretory dynamics in adolescent girls with anorexia nervosa and effectson bone metabolism. J. Clin. Endocrinol. Metab., 2004; 89: 4972-4980
  Google Scholar
• 35. Misra M., Miller K.K., Kuo K., Griffin K., Stewart V., Hunter E., HerzogD.B., Klibanski A.: Secretory dynamics of leptin in adolescent girls withanorexia nervosa and healthy adolescents. Am. J. Physiol. Endorcinol.Metab., 2005; 289: E373-E381
  Google Scholar
• 36. Monteleone P., Martiadis V., Colurcio B., Maj M.: Leptin secretionis related to chronicity and severity of the illness in bulimia nervosa.Psychosom. Med., 2002; 64: 874-879
  Google Scholar
• 37. Müller T.D., Föcker M., Holtkamp K., Herpertz-Dahlmann B., HebebrandtJ.: Leptin-mediated neuroendocrine alterations in anorexianervosa: somatic and behavioral implications. Child. Adolesc. Psychiatr.Clin. N. Am., 2009; 18: 117-129
  Google Scholar
• 38. Nakai Y., Hamagaki S., Kato S., Seino Y., Tagaki R., Kurimoto F.: Role ofleptin in women with eating disorders. Int. J. Eat. Disord., 1999; 26: 29-35
  Google Scholar
• 39. Nedvidkova J., Papezova H., Haluzik M., Schreiber V.: Interactionbetween serum leptin levels and hypothalamo-hypophyseal-thyroidaxis in patients with anorexia nervosa. Endocr. Res., 2000; 26: 219-230
  Google Scholar
• 40. Nishimura H., Komaki G., Ando T., Nakahara T., Oka T., Kawai K.,Nagata T., Nishizono A., Okamoto Y., Okabe K., Koide M., Yamaguchi C.,Saito S., Ohkuma K., Nagata K. et al.: Psychological and weight-relatedcharacteristics of patients with anorexia nervosa-restricting type wholater develop bulimia nervosa. Biopsychosoc. Med., 2008; 2: 5
  Google Scholar
• 41. Nogal P., Pniewska-Siark B., Lewiński A.: Evaluation of selected clinicaland diagnostic parameters in girls with anorexia nervosa (I). Neuro.Endocrinol. Lett., 2008; 29: 421-427
  Google Scholar
• 42. Oświęcimska J., Ziora K., Geisler G., Broll-Waśka K.: Prospectiveevaluation of leptin and neuropeptide Y (NPY) serum levels in girls withanorexia nervosa. Neuro Endocrinol. Lett., 2005; 26: 301-304
  Google Scholar
• 43. Polivy J., Herman C.P.: Causes of eating disorders. Annu. Rev. Psychol.,2002; 53: 187-213
  Google Scholar
• 44. Reinehr T., Isa A., de Sousa G., Dieffenbach R., Andler W.: Thyroidhormones and their relation to weight status. Horm. Res., 2008; 70: 51-57
  Google Scholar
• 45. Robertson S.A., Leinninger G.M., Myers M.G.Jr.: Molecular and neuralmediators of leptin action. Physiol. Behav., 2008; 94: 637-642
  Google Scholar
• 46. Scacchi M., Pincelli I.A., Caumo A., Tomasi P., Delitala G., Baldi G.,Cavagnini F.: Spontaneous nocturnal growth hormone secretion in anorexianervosa. J. Clin. Endocrinol. Metab., 1997; 82: 3225-3229
  Google Scholar
• 47. Scacchi M., Pincelli I.A., Cavagnini F.: Nutritional status in the neuroendocrinecontrol of growth hormone secretion: the model of anorexianervosa. Front. Neuroendocrinol., 2003; 24: 200-224
  Google Scholar
• 48. Śmiarowska M., Białecka M., Korwin-Piotrowska K.: Molecular mediatorsin control of food consumption and energy balance in eatingdisorders. Adv. Clin. Exp. Med., 2007; 16: 569-576
  Google Scholar
• 49. Śmiarowska M., Horodnicki J., Samochowiec J., Milewicz A.: Theleptin and some neuropeptides secretion in patients with eating disorders.World J. Biol. Psychiatry, 2002; 2: 230S
  Google Scholar
• 50. Støving R.K., Chen J.W., Glintborg D., Brixen K., Flyvbjerg A., HørderK., Frystyk J.: Bioactive insulin-like growth factor (IGF) I and IGF-bindingprotein-1 in anorexia nervosa. J. Clin. Endocrinol. Metab., 2007;92: 2323-2329
  Google Scholar
• 51. Støving R.K., Hangaard J., Hansen-Nord M., Hagen C.: A review of endocrinechanges in anorexia nervosa. J. Psychiatr. Res., 1999; 33: 139-152
  Google Scholar
• 52. Støving R.K., Veldhuis J.D., Flyvbjerg A., Vinten J., Hangaard J., KoldkjaerO.G., Kristiansen J., Hagen C.: Jointly amplified basal and pulsatilegrowth hormone (GH) secretion and increased process irregularity inwomen with anorexia nervosa: indirect evidence for disruption of feedbackregulation within the GH-insulin-like growth factor I axis. J. Clin.Endocrinol. Metab., 1999; 84: 2056-2063
  Google Scholar
• 53. Tomova A., Makker K., Kirilov G., Agarwal A., Kumanov P.: Disturbancesin gonadal axis in women with anorexia nervosa. Eat. WeightDisord., 2007; 12: e92-e97
  Google Scholar
• 54. Walsh B.T., Devlin M.J.: Eating disorders: progress and problems.Science, 1998; 280: 1387-1390
  Google Scholar

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