Differences in cortisol concentrations in adolescents with eating disorders: a systematic review Please cite this article as: Luz Neto LM, Vasconcelos FM, Silva JE, Pinto TC, Sougey ÉB, Ximenes RC. Differences in cortisol concentrations in adolescents with eating disorders: a systematic review. J Pediatr (Rio J). 2019;95:18–26.

Laércio Marques da Luz Neto Flávia Maria Nassar de Vasconcelos Jacqueline Elineuza da Silva Tiago Coimbra Costa Pinto Éverton Botelho Sougey Rosana Christine Cavalcanti Ximenes About the authors

Abstract

Objective:

To perform a systematic review of the literature for scientific evidence of possible differences in cortisol concentrations in adolescents with eating disorders.

Source of data:

Electronic searches were conducting in the PubMed, Scientific Electronic Library Online, Virtual Health Library, and Science Direct databases for articles published between 2007 and 2017 using the keywords, cortisol, hydrocortisone; eating disorders, bulimia, bulimia nervosa, anorexia, anorexia nervosa; adolescence, adolescent, adolescents.

Synthesis of data:

A total of 192 articles were found. After the analysis of the eligibility criteria using the PRISMA method, 19 articles were selected for the present review. Most studies were conducted in Europe. Adolescents diagnosed with anorexia nervosa were evaluated in all studies, except one, when other eating disorders were investigated. Blood was the means used for the determination of cortisol. In ten studies, cortisol levels were higher in the group with anorexia than the control group and a reduction in cortisol levels occurred in the adolescents after being submitted to nutritional recovery.

Conclusions:

Patients with eating disorders may have several clinical consequences, such as changes in body fat distribution, changes in bone mineral density, worsening of neurocognitive ability, and endocrine changes (e.g., hypercortisolemia), which in turn can lead to hyperglycemia, insulin resistance, hypertension, and increased risk of infections. The findings demonstrate that adolescents with eating disorders, especially anorexia nervosa, have increased cortisol levels, which are reduced after the treatment period. Further studies on differences in cortisol concentrations in adolescents with other eating disorders are needed, using different methods.

KEYWORDS
Cortisol; Eating disorders; Anorexia; Anorexia nervosa; Adolescent

Resumo

Objetivo:

Realizar uma análise sistemática da literatura em busca de evidências científicas de possíveis diferenças nas concentrações de cortisol em adolescentes com transtornos alimentares.

Fonte de dados:

Pesquisas eletrônicas foram realizadas nas bases de dados do Pubmed, da Scientific Electronic Library Online, da Biblioteca Virtual da Saúde e do Science Direct em busca de artigos publicados entre 2007 e 2017 que utilizaram as palavras-chave: cortisol, hidrocortisona, transtornos alimentares, bulimia, bulimia nervosa, anorexia, anorexia nervosa, adolescência, adolescente e adolescentes.

Síntese dos dados:

Foram encontrados 192 artigos. Após a análise dos critérios de elegibilidade utilizando o método PRISMA, 19 artigos foram selecionados para esta análise. A maioria dos estudos foi realizada na Europa. Os adolescentes diagnosticados com anorexia nervosa foram avaliados em todos os estudos, com exceção de um, em que outros transtornos alimentares foram investigados. A coleta de sangue foi o meio utilizado para a determinação do cortisol. Em dez estudos, os níveis de cortisol estavam mais elevados no grupo com anorexia do que no grupo de controle e ocorreu uma redução nos níveis de cortisol nos adolescentes após serem submetidos a uma recuperação nutricional.

Conclusões:

Os pacientes com transtornos alimentares podem apresentar diversas consequências clínicas, como alterações na distribuição de gordura corporal, alterações na densidade mineral óssea, piora da capacidade neurocognitiva e alterações endócrinas, como a hipercortisolemia que, por sua vez, pode levar à hiperglicemia, resistência à insulina, hipertensão e ao aumento do risco de infecções. Os achados demonstraram que os adolescentes com transtornos alimentares, principalmente a anorexia nervosa, apresentaram níveis mais elevados de cortisol, que são reduzidos após o período de tratamento. São necessários estudos adicionais sobre as diferenças nas concentrações de cortisol em adolescentes com outros transtornos alimentares, utilizando meios diferentes.

PALAVRAS-CHAVE
Cortisol; Transtornos alimentares; Anorexia; Anorexia nervosa; Adolescente

Introduction

According to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), eating disorders are characterized by severe disturbances in eating behavior and have a multifactor etiology involving genetic predisposition as well as socio-cultural, biological, and psychological influences.11 American Psychiatry Association (APA). Diagnostic and statistical manual of mental disorders - DSM-5. 5th ed. Washington: APA; 2013. Behaviors related to eating disorders, such as perpetual dieting, the desire to be thinner, or compensatory behavior (self-induced vomiting and excessive exercise) are frequently observed in young women.22 Murray K, Rieger E, Bryne D. The relationship between stress and body satisfaction in female and male adolescents. Stress Health. 2015;31:13-23.

The World Health Organization (WHO) defines adolescence as the second decade of life (10–19 years).33 World Health Organization. Addressing the socioeconomic determinants of healthy eating habits and physical activity levels among adolescents; 2006. Available from: http://www.euro.who.int/data/assets/pdffile/0005/98231/e89375.pdf [cited 18.03.13].
http://www.euro.who.int/data/assets/pdff...
Mäkinen et al.44 Mäkinen M, Marttunen M, Komulainen E, Terevnikov V, Puukko-Viertomies LR, Aalberg V, et al. Development of self-image and its components during a one-year follow-up in non-referred adolescents with excess and normal weight. Child Adolesc Psychiatry Ment Health. 2015;9:5. describe adolescence as a phase of life marked by profound physical, cognitive, emotional, and social changes that require adaptations to the adoption of new practices, behaviors, and autonomy for adult life. Therefore, adolescence is a period in which individuals are highly susceptible to various behavioral disorders, including eating.

Stress has been identified as a potential risk factor for the development of eating disorders.55 Jacobi C, Hayward C, de Zwaan M, Kraemer HC, Agras WS. Coming to terms with risk factors for eating disorders: application of risk terminology and suggestions for a general taxonomy. Psychol Bull. 2004;130:19-65. There is evidence that patients often experience severe chronic stress stemming from life events prior to the onset of said disorders.66 Rojo L, Conesa L, Bermudez O, Livianos L. Influence of stress in the onset of eating disorders: data from a two-stage epidemiologic controlled study. Psychosom Med. 2006;68:628-35. Cortisol is one of the steroidal hormones directly related to high levels of stress. Preliminary studies offer evidence that patients with anorexia nervosa present high levels of cortisol due to the association between these disorders and behavioral characteristics (high levels of depression and stress). In addition, hypercortisolemia, elevation of urinary free cortisol, and alteration of the circadian rhythm of cortisol may be present in patients with normal weight who present with bulimia nervosa77 American Psychiatric Association Work Group on Eating Disorders. Practice guidelines for the treatment of patients with eating disorders [revision]. Am J Psychiatry. 2000;157:1-39.; moreover, patients with unspecified eating disorders also have higher cortisol levels than their corresponding controls.88 Schneider LF, Warren MP. Functional hypothalamic amenorrhea is associated with elevated ghrelin and disordered eating. Fertil Steril. 2006;86:1744-9.1010 Warren MP, Voussoughian F, Geer EB, Hyle EP, Adberg CL, Ramos RH. Functional hypothalamic amenorrhea: hypoleptinemia and disordered eating. J Clin Endocrinol Metab. 1999;84:873-7. Cortisol is one of the most abundant androgenic hormones in the body and is increased in the presence of physical and/or psychological stress. Elevated cortisol can trigger psycho-physiological reactions that result in hyperfunctioning of the sympathetic nervous system and endocrine system, specifically the adrenal glands.1111 Santos AF, Santos LA, Melo DO, Júnior AA. Estresse e estratégias de enfrentamento em pacientes que serão submetidos à cirurgia de colecistectomia. Interação em Psicol. 2006;10:63-73.,1212 Díaz-Marsá M, Carrasco JL, López-Ibor M, Moratti S, Montes A, Ortiz T. Orbitofrontal dysfunction related to depressive symptomatology in subjects with borderline personality disorder. J Affect Disord. 2011;134:410-5. It is produced by the adrenal gland, which is involved in the response to stress and may play an important role in eating behavior, in addition to being associated with increased energy intake in healthy individuals. The production of cortisol has a circadian rhythm that depends on the stimulation of the adrenocorticotropic hormone (ACTH). Its level is higher near the beginning of daily activities, decreasing over the 24 h.1313 Laposky AD, Bass J, Kohsaka A, Turek FW. Sleep and circadian rhythms: key components in the regulation of energy metabolism. FEBS Lett. 2008;582:142-51.

Although the clinical manifestations of hypercortisolemia in patients with anorexia nervosa may appear inconsistent with those observed in patients with Cushing's syndrome, upon further examination several parallels can be observed.1414 Miller KK. Endocrine dysregulation in anorexia nervosa update. J Clin Endocrinol Metab. 2011;96:2939-49. Blood cortisol levels at night are inversely associated with bone mineral density and positively associated with the severity of depression and anxiety symptoms in women with anorexia nervosa.1515 Lawson EA, Donoho D, Miller KK, Misra M, Meenaghan E, Lydecker J, et al. Hypercortisolemia is associated with severity of bone loss and depression in hypothalamic amenorrhea and anorexia nervosa. J Clin Endocrinol Metab. 2009;94:4710-6. As cortisol stimulates gluconeogenesis, an increase in cortisol concentrations, in addition to high levels of GH, may be another adaptive mechanism to maintain euglycemia in this condition of severe malnutrition. In addition, glucocorticoids are endogenous antagonists of leptin and insulin.1616 Misra M, Klibanski A. Neuroendocrine consequences of anorexia nervosa in adolescents. Endocr Dev. 2010;17:197-214.

Usually, there is an excellent association between cortisol production and the activity of the hypothalamic-pituitary-adrenocortical (HPA) axis, being easily detected in saliva, blood, and urine. Cortisol can be considered as an excellent biomarker of HPA axis function and, consequently, of the study of the effects of stress in humans.1717 Hellhammer J, Wust S, Kudielka BM. Salivary cortisol as a biomarker in stress research. Psychoneuroendocrinology. 2009;34:163-71. Repeated and prolonged activation of certain systems, including HPA axis, will put individuals at greater risk of developing physical (e.g., myocardial infarction, multiple sclerosis, abdominal pain, menstrual disorders, viral infections, diabetes, arthritis rheumatoid, and cancer) and psychological disorders (e.g., depression, schizophrenia, anxiety, and cancer).1818 Dougall AL. Stress, health and illness. In: Baum A, Revenson T, Singer J, editors. Handbook of health psychology. London: Lawrence Erlbaum Associates; 2001. p. 321-36.

Considering the importance of hormonal changes that occur as clinical complications of patients with eating disorders as well as the relationship of such changes with the maintenance of these disorders, the aim of the present study was perform a systematic review of the literature on differences in cortisol concentrations in adolescents with eating disorders.

Methods

Configuration and registry of study

The methods employed for the present study were based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The protocol for this review was registered with the International Prospective Register of Systematic Reviews (PROSPERO), under reference number CRD42017067630. The articles selected for review were submitted to an interpretative analysis directed by the guiding question.

Search strategy

Three reviewers searched for articles published in journals indexed in the PubMed, Scientific Electronic Library Online (Scielo), Biblioteca Virtual de Saúde (Bireme) and ScienceDirect databases. The following key words were employed: hydrocortisone OR cortisol AND “eating disorders” OR anorexia OR “anorexia nervosa” OR bulimia OR “bulimia nervosa” AND adolescents OR adolescent OR adolescence (Mesh).

Selection criteria

Studies were selected for the present systematic review based on the following inclusion criteria: epidemiological studies (cross-sectional, case–control, cohort, and clinical trial) that evaluated the concentration of cortisol in adolescents with eating disorders published between 2007 and 2017. Epidemiological studies not related to the topic of interest, experimental studies, letters to the editor, case studies, literature reviews, and studies involving animals were excluded.

Results

The electronic search led to the retrieval of 192 articles (Fig. 1). One of the articles had been accepted for publication, but the full text had not yet been published. After the removal of duplicates, the articles were read and analyzed by three independent reviews, who had undergone a training and calibration exercise. A total of 102 articles were excluded for not addressing the topic of interest, not analyzing cortisol, not addressing eating disorders, or involving adults. After the exclusion of review articles, case reports, case series, letters to the editor, and studies involving animals, 19 articles were selected for review (Table 1) and analyzed based on previously established categories. Seven categories were considered: location in which the study was conducted; year of publication; sample selected; type of eating disorder; methods for diagnosing eating disorder; methods for collecting and analyzing cortisol; and cortisol results with comparison between group with eating disorder and healthy control group.

Figure 1
Flowchart of the process of article selection for systematic review based on eligibility criteria.

Table 1
Characteristics of the 19 studies on the changes in cortisol in adolescents with eating disorders included in this review.

Most studies (n = 14) were conducted in Europe.1919 Föcker M, Stalder T, Kirschbaum C, Albrecht M, Adams F, de Zwaan M. Hair cortisol concentrations in adolescent girls with anorexia nervosa are lower compared to healthy and psychiatric controls. Eur Eat Disord Rev. 2016;24:531-5.3232 Oświecimska J, Ziora K, Adamczyk P, Roczniak W, Pikiewicz-Koch A, Stojewska M, et al. Effects of neuroendocrine changes on results of ambulatory blood pressure monitoring (ABPM) in adolescent girls with anorexia nervosa. Neuro Endocrinol Lett. 2007;28:410-6. Three studies were conducted in the Americas,3333 Pitts S, Blood E, Divasta A, Gordon CM. Percentage body fat by dual-energy X-ray absorptiometry is associated with menstrual recovery in adolescents with anorexia nervosa. J Adolesc Health. 2014;54:739-41.3535 Misra M, Miller KK, Cord J, Prabhakaran R, Herzog DB, Goldstein M, et al. Relationships between serum adipokines, insulin levels, and bone density in girls with anorexia nervosa. J Clin Endocrinol Metab. 2007;92:2046-52. and two studies were conducted in Asia.3636 Levy-Shraga Y, David D, Vered I, Kochavi B, Stein D, Modan-Moses D. Hyponatremia and decreased bone density in adolescent inpatients diagnosed with anorexia nervosa. Nutrition. 2016;32:1097-1102.,3737 Shibuya I, Nagamitsu S, Okamura H, Komatsu H, Ozono S, Yamashita Y, et al. Changes in salivary cortisol levels as a prognostic predictor in children with anorexia nervosa. Int J Psychophysiol. 2001;82:196-201. The year with the largest number of publications (n = 4) was 2012.2222 Bühren K, Mainz V, Herpertz-Dahlmann B, Schäfer K, Kahraman-Lanzerath B, Lente C. Cognitive flexibility in juvenile anorexia nervosa patients before and after weight recovery. J Neural Transm (Vienna). 2012;119:1047-57.2525 Oskis A, Loveday C, Hucklebridge F, Thorn L, Clow A. Diurnal patterns of salivary cortisol and DHEA in adolescent anorexia nervosa. Stress. 2012;15:601-7. All studies involved female adolescents and three also involved male adolescents.2828 Castro-Fornieles J, Bargalló N, Lázaro L, Andrés S, Falcon C, Plana MT, et al. A cross-sectional and follow-up voxel-based morphometric MRI study in adolescent anorexia nervosa. J Psychiatr Res. 2009;43:331-40.,3030 Castro-Fornieles J, Deulofeu R, Baeza I, Casulà V, Saura B, Lázaro L, et al. Psychopathological and nutritional correlates of plasma homovanillic acid in adolescents with anorexia nervosa. J Psychiatr Res. 2008;42:213-20.,3131 Castro-Fornieles J, Bargalló N, Lázaro L, Andrés S, Falcon C, Plana MT, et al. Adolescent anorexia nervosa: cross-sectional and follow-up frontal gray matter disturbances detected with proton magnetic resonance spectroscopy. J Psychiatr Res. 2007;41:952-8.

Regarding the collection method, cortisol levels were evaluated in blood samples in most studies (n = 14).2121 Ostrowska Z, Ziora K, Oświęcimska J, Wołkowska-Pokrywa K, Szapska B. Assessment of the relationship between melatonin, hormones of the pituitary-ovarian, -thyroid and -adrenocortical axes, and osteoprotegerin and its ligand sRANKL in girls with anorexia nervosa. Postepy Hig Med Dosw (online). 2013;67:433-41.,2222 Bühren K, Mainz V, Herpertz-Dahlmann B, Schäfer K, Kahraman-Lanzerath B, Lente C. Cognitive flexibility in juvenile anorexia nervosa patients before and after weight recovery. J Neural Transm (Vienna). 2012;119:1047-57.,2424 Mainz V, Schulte-Rüther M, Fink GR, Herpertz-Dahlmann B, Konrad K. Structural brain abnormalities in adolescent anorexia nervosa before and after weight recovery and associated hormonal changes. Psychosom Med. 2012;74:574-82.,2626 Buehren K, Konrad K, Schaefer K, Kratzsch J, Kahraman-Lanzerath B, Lente C, et al. Association between neuroendocrinological parameters and learning and memory functions in adolescent anorexia nervosa before and after weight recovery. J Neural Transm (Vienna). 2011;118:963-8.3636 Levy-Shraga Y, David D, Vered I, Kochavi B, Stein D, Modan-Moses D. Hyponatremia and decreased bone density in adolescent inpatients diagnosed with anorexia nervosa. Nutrition. 2016;32:1097-1102. Cortisol was measured in saliva samples in four studies2020 Paszynska E, Dmitrzak-Weglarz M, Tyszkiewicz-Nwafor M, Slopien A. Salivary alpha-amylase, secretory IgA and free cortisol as neurobiological components of the stress response in the acute phase of anorexia nervosa. World J Biol Psychiatry. 2016;17:266-73.,2323 Ginty AT, Phillips AC, Higgs S, Heaney JL, Carroll D. Disordered eating behaviour is associated with blunted cortisol and cardiovascular reactions to acute psychological stress. Psychoneuroendocrinology. 2012;37:715-24.,2525 Oskis A, Loveday C, Hucklebridge F, Thorn L, Clow A. Diurnal patterns of salivary cortisol and DHEA in adolescent anorexia nervosa. Stress. 2012;15:601-7.,3737 Shibuya I, Nagamitsu S, Okamura H, Komatsu H, Ozono S, Yamashita Y, et al. Changes in salivary cortisol levels as a prognostic predictor in children with anorexia nervosa. Int J Psychophysiol. 2001;82:196-201. and in hair follicles in one study.1616 Misra M, Klibanski A. Neuroendocrine consequences of anorexia nervosa in adolescents. Endocr Dev. 2010;17:197-214. Regarding the time of sampling, most studies (n = 11) collected the hormone exclusively in the morning period.2020 Paszynska E, Dmitrzak-Weglarz M, Tyszkiewicz-Nwafor M, Slopien A. Salivary alpha-amylase, secretory IgA and free cortisol as neurobiological components of the stress response in the acute phase of anorexia nervosa. World J Biol Psychiatry. 2016;17:266-73.2222 Bühren K, Mainz V, Herpertz-Dahlmann B, Schäfer K, Kahraman-Lanzerath B, Lente C. Cognitive flexibility in juvenile anorexia nervosa patients before and after weight recovery. J Neural Transm (Vienna). 2012;119:1047-57.,2424 Mainz V, Schulte-Rüther M, Fink GR, Herpertz-Dahlmann B, Konrad K. Structural brain abnormalities in adolescent anorexia nervosa before and after weight recovery and associated hormonal changes. Psychosom Med. 2012;74:574-82.,2626 Buehren K, Konrad K, Schaefer K, Kratzsch J, Kahraman-Lanzerath B, Lente C, et al. Association between neuroendocrinological parameters and learning and memory functions in adolescent anorexia nervosa before and after weight recovery. J Neural Transm (Vienna). 2011;118:963-8.,2828 Castro-Fornieles J, Bargalló N, Lázaro L, Andrés S, Falcon C, Plana MT, et al. A cross-sectional and follow-up voxel-based morphometric MRI study in adolescent anorexia nervosa. J Psychiatr Res. 2009;43:331-40.3232 Oświecimska J, Ziora K, Adamczyk P, Roczniak W, Pikiewicz-Koch A, Stojewska M, et al. Effects of neuroendocrine changes on results of ambulatory blood pressure monitoring (ABPM) in adolescent girls with anorexia nervosa. Neuro Endocrinol Lett. 2007;28:410-6.,3636 Levy-Shraga Y, David D, Vered I, Kochavi B, Stein D, Modan-Moses D. Hyponatremia and decreased bone density in adolescent inpatients diagnosed with anorexia nervosa. Nutrition. 2016;32:1097-1102. Only one study did not evaluate adolescents with a diagnosis of anorexia nervosa.2323 Ginty AT, Phillips AC, Higgs S, Heaney JL, Carroll D. Disordered eating behaviour is associated with blunted cortisol and cardiovascular reactions to acute psychological stress. Psychoneuroendocrinology. 2012;37:715-24.

In ten of the studies, cortisol levels were higher in the group of adolescents with anorexia when compared with the control group.2020 Paszynska E, Dmitrzak-Weglarz M, Tyszkiewicz-Nwafor M, Slopien A. Salivary alpha-amylase, secretory IgA and free cortisol as neurobiological components of the stress response in the acute phase of anorexia nervosa. World J Biol Psychiatry. 2016;17:266-73.2222 Bühren K, Mainz V, Herpertz-Dahlmann B, Schäfer K, Kahraman-Lanzerath B, Lente C. Cognitive flexibility in juvenile anorexia nervosa patients before and after weight recovery. J Neural Transm (Vienna). 2012;119:1047-57.,2525 Oskis A, Loveday C, Hucklebridge F, Thorn L, Clow A. Diurnal patterns of salivary cortisol and DHEA in adolescent anorexia nervosa. Stress. 2012;15:601-7.2727 Ziora KT, Oswiecimska JM, Swietochowska E, Ostrowska Z, Stojewska M, Gorczyca P, et al. Assessment of serum levels resistin in girls with anorexia nervosa. Part II. Relationships between serum levels of resistin and thyroid, adrenal and gonadal hormones. Neuro Endocrinol Lett. 2011;32:697-703.,2929 Haas VK, Kohn MR, Clarke SD, Allen JR, Madden S, Müller MJ, et al. Body composition changes in female adolescents with anorexia nervosa. Am J Clin Nutr. 2009;89:1005-10.,3434 Misra M, Prabhakaran R, Miller KK, Goldstein MA, Mickley D, Clauss L, et al. Prognostic indicators of changes in bone density measures in adolescent girls with anorexia nervosa-II. J Clin Endocrinol Metab. 2008;93:1292-7.,3535 Misra M, Miller KK, Cord J, Prabhakaran R, Herzog DB, Goldstein M, et al. Relationships between serum adipokines, insulin levels, and bone density in girls with anorexia nervosa. J Clin Endocrinol Metab. 2007;92:2046-52.,3737 Shibuya I, Nagamitsu S, Okamura H, Komatsu H, Ozono S, Yamashita Y, et al. Changes in salivary cortisol levels as a prognostic predictor in children with anorexia nervosa. Int J Psychophysiol. 2001;82:196-201. In one study, cortisol levels were lower in the group of adolescents with anorexia than in the control group.1616 Misra M, Klibanski A. Neuroendocrine consequences of anorexia nervosa in adolescents. Endocr Dev. 2010;17:197-214. In three studies, cortisol was measured in a group of adolescents with anorexia, and no comparison with a control group was made.3232 Oświecimska J, Ziora K, Adamczyk P, Roczniak W, Pikiewicz-Koch A, Stojewska M, et al. Effects of neuroendocrine changes on results of ambulatory blood pressure monitoring (ABPM) in adolescent girls with anorexia nervosa. Neuro Endocrinol Lett. 2007;28:410-6.,3333 Pitts S, Blood E, Divasta A, Gordon CM. Percentage body fat by dual-energy X-ray absorptiometry is associated with menstrual recovery in adolescents with anorexia nervosa. J Adolesc Health. 2014;54:739-41.,3636 Levy-Shraga Y, David D, Vered I, Kochavi B, Stein D, Modan-Moses D. Hyponatremia and decreased bone density in adolescent inpatients diagnosed with anorexia nervosa. Nutrition. 2016;32:1097-1102. In four studies, the levels of this hormone were compared before and after treatment involving weight gain, and a reduction was found in the post-treatment evaluation.2424 Mainz V, Schulte-Rüther M, Fink GR, Herpertz-Dahlmann B, Konrad K. Structural brain abnormalities in adolescent anorexia nervosa before and after weight recovery and associated hormonal changes. Psychosom Med. 2012;74:574-82.,2828 Castro-Fornieles J, Bargalló N, Lázaro L, Andrés S, Falcon C, Plana MT, et al. A cross-sectional and follow-up voxel-based morphometric MRI study in adolescent anorexia nervosa. J Psychiatr Res. 2009;43:331-40.,3030 Castro-Fornieles J, Deulofeu R, Baeza I, Casulà V, Saura B, Lázaro L, et al. Psychopathological and nutritional correlates of plasma homovanillic acid in adolescents with anorexia nervosa. J Psychiatr Res. 2008;42:213-20.,3131 Castro-Fornieles J, Bargalló N, Lázaro L, Andrés S, Falcon C, Plana MT, et al. Adolescent anorexia nervosa: cross-sectional and follow-up frontal gray matter disturbances detected with proton magnetic resonance spectroscopy. J Psychiatr Res. 2007;41:952-8.

Discussion

The aim of the present study was to perform a systematic review of the literature regarding differences in cortisol concentrations in adolescents with eating disorders. The analysis of the articles confirms anorexia nervosa as the most widely studied eating disorder, especially in Europe. The main findings were the higher level of cortisol in adolescents with anorexia nervosa in comparison with healthy controls and the reduction in the levels of this hormone following weight recovery.

Anorexia nervosa is a condition of severe malnutrition that is prevalent among adolescent girls and young women, affecting 0.2–1% of this population.3838 Jaite C, Hoffmann F, Glaeske G, Bachmann CJ. Prevalence, comorbidities and outpatient treatment of anorexia and bulimia nervosa in German children and adolescents. Eat Weight Disord. 2013;18:157-65.4242 Wade TD, Bergin JL, Tiggemann M, Bulik CM, Fairburn CG. Prevalence and long-term course of lifetime eating disorders in an adult Australian twin cohort. Aust N Z J Psychiatry. 2006;40:121-8. Studies addressing this condition are more common than those addressing other eating disorders, which may be explained by the fact that the signs and symptoms are easier to detect. Moreover, the clinical complications of this condition are more severe and the mortality rate is higher. Anorexia nervosa is characterized by a distorted body image and very low body weight associated with the inability to gain or maintain weight; in women, the DSM-IV included amenorrhea for at least three menstrual cycles in the diagnostic criteria.4343 American Psychiatric Association (APA). Diagnostic and statistical manual of mental disorders. Washington: APA; 1987. However, the revised criteria on weight are less strict in the DSM-5, and amenorrhea is no longer necessary for the diagnosis.11 American Psychiatry Association (APA). Diagnostic and statistical manual of mental disorders - DSM-5. 5th ed. Washington: APA; 2013. Although most of the studies analyzed were conducted with adolescents with anorexia nervosa, the research attempted to include eating disorders in general.

Three articles analyzed in the present review also included males. Data on the prevalence of eating disorders in the male population are somewhat scarce. For many years, it was believed that eating disorders only affected the female population, and many evaluation tests have a gender bias, as they were created for women; therefore the prevalence of this problem is underestimated the male population.4444 Darcy A, Lin IH. Are we asking the right questions? A review of assessment of males with eating disorders. Eat Disord. 2012;20:416-26. The most widely cited study estimates prevalence rates of 0.3% for anorexia nervosa, 0.5% for bulimia nervosa, and 2% for binge eating disorder among males using the DSM-IV criteria.4040 Hudson JI, Hiripi E, Pope HG, Kessler RC. The prevalence and correlates of eating disorders in the National Comorbidity Survey Replication. Biol Psychiatry. 2007;61:348-58. Thus, males account for 25% of cases of anorexia and bulimia and 36% of cases of binge eating disorder. Regarding differences in cortisol levels between the sexes, some studies indicate that differences in the response to neurobiological stress favor men,4545 Gallucci WT, Baum A, Laue L, Rabin DS, Chrousos GP, Gold PW, et al. Sex differences in sensitivity of the hypothalamic-pituitary-adrenal axis. Health Psychol. 1993;12:420-5.,4646 Jezová D, Juránková E, Mosnárová A, Kriska M, Skultétyová I. Neuroendocrine response during stress with relation to gender differences. Acta Neurobiol Exp (Wars). 1996;56:779-85. but there have been many reports demonstrating the opposite effect,4747 Kajantie E, Phillips DI. The effects of sex and hormonal status on the physiological response to acute psychosocial stress. Psychoneuroendocrinology. 2006;31:151-78.,4848 Kudielka BM, Hellhammer DH, Wüst S. Why do we respond so differently? Reviewing determinants of human salivary cortisol responses to challenge. Psychoneuroendocrinology. 2009;34:2-18. while some do not report differences between the sexes.4949 Earle TL, Linden W, Weinberg J. Differential effects of harassment on cardiovascular and salivary cortisol stress reactivity and recovery in women and men. J Psychosom Res. 1999;46:125-41.,5050 Owens JF, Stoney CM, Matthews KA. Menopausal status influences ambulatory blood pressure levels and blood pressure changes during mental stress. Circulation. 1993;88:2794-802. In addition, other factors could influence this expression, among which neuropsychiatric disorders, such as anxiety, depression, and post-traumatic stress disorder, which are related to stress and are influenced by sex hormones and gonadal.5151 Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB. The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol. 1999;160:1-12.5454 Gold PW, Chrousos GP. Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states. Mol Psychiatry. 2002;7:254-75. Cortisol was measured in blood and saliva samples, and, in one study, hair follicles. Regardless of the type of collection, significant differences were found between the groups with eating disorders and healthy controls. However, the evaluation of hormone concentrations in saliva is more reliable, as the blood collection process in itself causes stress and can raise cortisol levels. Moreover, strong correlations have been found between salivary and serum cortisol in normal individuals at all ages, and samples remain stable when frozen for long periods of time. Hormone concentrations in saliva reflect the fraction not linked to carrier protein (free hormone fraction).5555 Sociedade Brasileira de Patologia Clínica/Medicina Laboratorial. Recomendações da Sociedade Brasileira de Patologia Clínica/Medicina Laboratorial (SBPC/ML): boas práticas em microbiologia clínica. São Paulo - Barueri, SP: Manole; 2015. One of the studies in the present review validated the use of salivary cortisol to investigate the activity of the HPA axis in adolescents with anorexia nervosa.3737 Shibuya I, Nagamitsu S, Okamura H, Komatsu H, Ozono S, Yamashita Y, et al. Changes in salivary cortisol levels as a prognostic predictor in children with anorexia nervosa. Int J Psychophysiol. 2001;82:196-201. According to a recent study, patients suffering from eating disorders show a blunted HPA axis reactivity to stress exposure and a generally reduced sympathetic/exaggerated parasympathetic nervous system activity, that is, the HPA axis interferes with the circadian cycle.5656 Het S, Vocks S, Wolf JM, Hammelstein P, Herpertz S, Wolf OT. Blunted neuroendocrine stress reactivity in young women with eating disorders. J Psychosom Res. 2015;78:260-7.

In ten studies, cortisol levels were compared between adolescent with anorexia and healthy controls, and higher levels were observed in the group with the eating disorder. Other studies have reported that anorexia nervosa is associated with a state of relative hypercortisolemia in adults and adolescents.1515 Lawson EA, Donoho D, Miller KK, Misra M, Meenaghan E, Lydecker J, et al. Hypercortisolemia is associated with severity of bone loss and depression in hypothalamic amenorrhea and anorexia nervosa. J Clin Endocrinol Metab. 2009;94:4710-6.,5757 Estour B, Germain N, Diconne E, Frere D, Cottet-Emard JM, Carrot G, et al. Hormonal profile heterogeneity and short-term physical risk in restrictive anorexia nervosa. J Clin Endocrinol Metab. 2010;95:2203-10.,5858 Lawson EA, Misra M, Meenaghan E, Rosenblum L, Donoho DA, Herzog D, et al. Adrenal glucocorticoid and androgen precursor dissociation in anorexia nervosa. J Clin Endocrinol Metab. 2009;94:1367-71. Elevated cortisol has multiple effects, such as reduction in bone mineral density5959 Baldock PA, Sainsbury A, Couzens M, Enriquez RF, Thomas GP, Gardiner EM, et al. Hypothalamic Y2 receptors regulate bone formation. J Clin Invest. 2002;109:915-21. and poorer cognitive performance.6060 Chui HT, Christensen BK, Zipursky RB, Richards BA, Hanratty MK, Kabani NJ, et al. Cognitive function and brain structure in females with a history of adolescent-onset anorexia nervosa. Pediatrics. 2008;122:e427-37. Elevated cortisol also promotes an increase in the release of free fatty acids due to lipolysis and lower activity of lipoprotein lipase, thereby causing an increase in insulin resistance and hyperglycemia.6161 Doweiko JP, Nompleggi DJ. The role of albumin in human physiology and pathophysiology. Part III: Albumin and disease states. JPEN J Parenter Enteral Nutr. 1991;15:476-83. Shibuya et al.3737 Shibuya I, Nagamitsu S, Okamura H, Komatsu H, Ozono S, Yamashita Y, et al. Changes in salivary cortisol levels as a prognostic predictor in children with anorexia nervosa. Int J Psychophysiol. 2001;82:196-201. concluded that a higher basal cortisol concentration may be an indicator of anorexia severity. Likewise, Estour et al.5757 Estour B, Germain N, Diconne E, Frere D, Cottet-Emard JM, Carrot G, et al. Hormonal profile heterogeneity and short-term physical risk in restrictive anorexia nervosa. J Clin Endocrinol Metab. 2010;95:2203-10. suggests that cortisol could be used as an important prognostic predictor. However, levels rarely exceed double the upper limit of normality. Individuals with a low body mass index and low levels of fat mass, fasting glucose, and insulin have higher levels of cortisol, which is consistent with the theory that an increase in cortisol is an adaptation mechanism to maintain normoglycemia in a state of low energy availability.6262 Misra M, Klibanski A. Endocrine consequences of anorexia nervosa. Lancet Diabetes Endocrinol. 2014;2:581-92.

The increase in cortisol levels in adolescents with anorexia is due to hyperactivity of the HPA axis,6363 Lo Sauro C, Ravaldi C, Cabras PL, Faravelli C, Ricca V. Stress, hypothalamic–pituitary–adrenal axis and eating disorders. Neuropsychobiology. 2008;57:95-115. which results in the release of cortisol from the adrenal glands. Studies have demonstrated an increase in salivary or serum levels of cortisol in the acute phase of anorexia,6464 dos Santos E, dos Santos JE, Ribeiro RP, Rosa E, Silva AC, Moreira AC, et al. Absence of circadian salivary cortisol rhythm in women with anorexia nervosa. J Pediatr Adolesc Gynecol. 2007;20:13-8.6666 Gold PW, Gwirtsman H, Avgerinos PC, Nieman LK, Gallucci WT, Kaye W, et al. Abnormal hypothalamic–pituitary–adrenal function in anorexia nervosa. Pathophysiologic mechanisms in underweight and weight-corrected patients. N Engl J Med. 1986;314:1335-42. and it has been suggested that this situation is a biological adaptation to hunger as a consequence of chronic food restriction.3737 Shibuya I, Nagamitsu S, Okamura H, Komatsu H, Ozono S, Yamashita Y, et al. Changes in salivary cortisol levels as a prognostic predictor in children with anorexia nervosa. Int J Psychophysiol. 2001;82:196-201. The reduction in cortisol levels following weight recovery lends support to this theory.

In the present study, only changes in cortisol in adolescents with eating disorders were considered. It is possible that an analysis involving adults could offer conflicting results regarding cortisol levels.

Conclusions

Adolescents with anorexia nervosa have higher levels of cortisol (serum or salivary) than healthy controls. Elevated cortisol has many consequences, including low bone mineral density and a poorer cognitive performance. A very low frequency of other eating disorders, such as bulimia nervosa, was found in the studies analyzed, the results of which could be conflicting when compared with patients with anorexia nervosa. The main difficulty in diagnosing bulimia is the lack of significant weight loss, which differs from anorexia.

The increase in cortisol in adolescents with anorexia nervosa raises questions regarding the extent to which this population may suffer the consequences of this condition in the long term and whether such changes (i.e., hyperglycemia and hyperinsulinemia) persist even after weight recovery and the normalization of the levels of this hormone.

  • Please cite this article as: Luz Neto LM, Vasconcelos FM, Silva JE, Pinto TC, Sougey ÉB, Ximenes RC. Differences in cortisol concentrations in adolescents with eating disorders: a systematic review. J Pediatr (Rio J). 2019;95:18–26.

Acknowledgments

The authors are grateful to the Council for the Advancement of Higher Education Personnel (CAPES) for funding this study and the researchers of the Eating Disorders and Behaviors Research Group of the Federal University of Pernambuco (UFPE).

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Publication Dates

  • Publication in this collection
    Jan-Feb 2019

History

  • Received
    19 Jan 2018
  • Accepted
    24 Feb 2018
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