Disorders of eating behavior: Correlationbetween hypothalamo-pituitary–thyroidfunction and psychopathological aspects

Francesca Brambillaa,*, Paolo Santonastasob, Lorenza Caregaroc,Angela Favarob

aMental Health Department, Center for Study and Treatment of Eating Disorders,L. Sacco Hospital, Milan 20129, ItalybCenter for Study and Treatment of Eating Disorders, University Department of Neuroscience, Padua, ItalycUniversity Department of Clinical and Experimental Medicine, Padua, Italy

Received 7 February 2005; received in revised form 18 June 2005; accepted 19 June 2005

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KEYWORDSTSH;FT4;FT3;EDI-2;HSCL-90;Psychopathology;BMI

06-4530/$ - see front matter Q 200i:10.1016/j.psyneuen.2005.06.003

* Corresponding author. Address: Cinologia, Piazza Grandi 3, Milano 2020; fax: C 39 02 7012 2889.E-mail address: francesca.brambill

Summary Altered pituitary–thyroid (PT) function (TSH, FT4, FT3 plasma levels)was correlated with symptoms of Eating Disorders (ED) in 137 patients (65 ANR, 12ANP, 19 ANBP, 26 BN, 8 EDNOS-AN, 7 EDNOS-BN) and 30 controls. PT hormoneconcentrations were assessed by immunofluorimetry and psychopathology by EDI-2and HSCL-90. Values of TSH were decreased in ANP, BN, EDNOS-AN, of T4 in ANR,ANP, AN-BP, of T3 in ANR, ANP, ANBP, BN, EDNOS-AN, EDNOS-BN. TSH valuescorrelated negatively with ineffectiveness in BN and EDNOS-AN, and with depressionin EDNOS-AN. FT4 values correlated positively with perfectionism in ANR, ANP andANBP, with interoceptive awareness in EDNOS-AN, and negatively with depression inEDNOS-AN and with body dissatisfaction in EDNOS-BN. FT3 values correlatedpositively with perfectionism in ANBP and BN, with ineffectiveness in ANR andANP, with depression in EDNOS-AN, with hostility in ANR and EDNOS-BN, withinterpersonal sensibility in ANP, with somatization in EDNOS-BN, and negatively withinterpersonal distrust in EDNOS-AN. Prospective studies are needed to confirmwhether or not altered PT parameters correlate with ED symptoms during the courseof the diseases.Q 2005 Elsevier Ltd. All rights reserved.

5 Elsevier Ltd. All rights reserv

entro di Psiconeuroendo-19, Italy. Tel.: C39 02 717

a4@tin.it (F. Brambilla).

1. Introduction

Altered hypothalamo-pituitary–thyroid (HPT) func-tion has been observed in Eating Disorders (ED).Decreased circulating concentrations of triio-dothyronine (T3), free-triiodothyronine (FT3),with increased levels of biologically inactivereverse T3, and thyroxine-stimulating hormone

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(TSH) have been reported in Anorexia Nervosa (AN),while in Bulimia Nervosa (BN) lower than normalFT3, thyroxine (T4) and free-thyroxine (FT4)concentrations have been occasionally observed(Miyai et al., 1975; Travaglini et al., 1976; Wakelinget al., 1979; Pirke et al., 1985; Casper, 1986;Kiyohara et al., 1988; Kaplan et al., 1989; Spalteret al., 1993; Altemus et al., 1996; Gendall et al.,2003). Central modulation of TSH secretion isderanged in both AN and BN, as shown by lowerthan normal or even blunted and time-delayed TSHresponses to exogenous administration of thyrotro-pin-releasing hormone (TRH) (Vigersky and Loriaux,1977; Macaron et al., 1978; Wakeling et al., 1979;Casper and Frohman, 1982; Mitchell and Bantle,1983; Gwirtsman et al., 1983; Norris et al., 1985;Kiriike et al., 1987; Fichter et al., 1990; Baranowskaet al., 1999). Impaired HPT function has beententatively connected with low hypothalamicsecretion of TRH, as demonstrated by the lowcerebrospinal fluid (CSF) concentrations of thehormone (Lesem et al., 1994). These alterationshave been considered a consequence of starvation,in particular of carbohydrate deficiency, and of thedecreased resting energy expenditure in AN and ofmalnutrition in BN, since they appear also in non-anorexic malnourished individuals and even innormal subjects after a few days of starvationwithout a really significant weight loss, anddisappear after normalization of eating habits(Spaulding et al., 1976; Leslie et al., 1978; Wakelinget al., 1979; Moshang and Utiger, 1977; Vagenukis,1977; Fichter and Pirke, 1984).

Impairments of HPT function are known toprofoundly alter the developing and the maturebrain, influencing cognition and emotions, inparticular depression and anxiety, via a stimulatoryeffect on neuronal growth and differentiation, amodulation of neurotransmitter functions (mainlyserotonine (5-HT), noradrenaline (NE), dopamine(DA), acethylcholine (Ach)), and on the pre–postsynaptic receptor sensitivity (Plotnikoff et al.,1975; Funatsu et al., 1985; Molchan et al., 1990,1991; Kasparov et al., 1994; Hauser, 1994; Larsenet al., 1998; Bauer et al., 2003; Strawn et al., 2004;Van Boxtel et al., 2004; Larisch et al., 2004).Despite the well-established relationship betweenHPT secretion and neurotransmitter functions, sofar no data have been obtained in ED regarding thespecific effects that impaired HPT can exert on thebrain biochemistry of anorexic and bulimicpatients, and, subsequently, on the development,course, prognosis of the disorders, and on theappearance and persistence of specific psycho-pathological symptoms in these patients.

In a preliminary, transversal study of a mixedgroup of ED patients, we measured pituitary–thyroid (PT) hormones plasma concentrationsand in parallel we investigated the psychopatholo-gical aspects of the patients, to determine whetheror not significant relationships could be observedbetween biological and psychological impairments.With our study we wanted to see whether or not theputative PT dysfunctions observed in AN and BN,and occasionally in Non Otherwise Specified EatingDisorders anorexic and bulimic type patients(EDNOS-AN and BN) could possibly be connectedwith the pathogenesis of specific symptoms of thedisorders. In particular, we wanted to see whetheror not PT dysfunctions could modulate depression,anxiety or some of the mood-related psychopatho-logical aspects of ED, as demonstrated by Baueret al. (2003) and Larisch et al. (2004) in endocrineand mental disorders. If so, then, PT dysfunctionmay need to be corrected as fast as possible,possibly through nutritional rehabilitation or otherappropriate treatments, to separate the hormonalfrom the non-hormonal linked psychopathology andto direct treatments toward the correction of non-hormonal-dependent psychological impairments.

2. Material and methods

2.1. Subjects

Hundred and thirty-seven female patients with EDentered the study. They were 96 anorexics(65 restricted anorexics (ANR), 19 bingeing-purginganorexics (ANBP), 12 purging anorexics withoutbingeing (ANP), 26 bulimics ((BN) including purgingand non-purging but not long-lasting dietingpatients), 8 subjects with EDNOS-anorectic type(EDNOS-AN), and 7 with EDNOS-bulimic type(EDNOS-BN). The subjects were recruited over aperiod of 2 years at the Centers for the Study andTreatment of Eating Disorders of the UniversityInstitute of Psychiatry, Padua, Italy and of the SaccoHospital, Milan, Italy. Consensus diagnoses accord-ing to the DSM IV criteria (American PsychiatricAssociation, 1994) were obtained by senior psychia-trists who assessed the patients by clinical inter-views and by the Structured Clinical Interview forthe DSM IV (SCID; Spitzer, 1994). Thirty physicallyhealthy female volunteers, matched for age withthe patients, recruited from the hospital staff,formed the control group. They were also inter-viewed with the SCID to exclude present or lifetimeAxis I and II disorders. Patients and controls gaveinformed consent to participate in the study, afteran extensive description of its protocol. Exclusion

Table 1 Demographic data of patients with eating disorders and of controls.

Patients no. Age (yrs) Onset (yrs) Duration (ms) BMI

ANR 65 21.3G4.7 17.9G4.2 27.2G3.0 13.5G1.8ANP 19 27.2G9.6 21.3G10.4 37.4G17.0 15.6G1.3ANBP 12 23.0G5.3 18.7G3.5 35.2G50.5 15.0G1.7BN 26 26.3G7.0 20.3G6.5 47.2G63.8 20.5G2.1EDNOS-AN 8 22.0G0.0 18.1G2.5 33.6G46.6 18.3G1.0EDNOS-BN 7 23.2G4.7 19.0G3.9 41.1G24.8 20.1G2.2Controls 30 23.2G3.1 21.2G1.3

ANR, restricted anorexics; ANP, purging anorexics; ANBP, bingeing-purging anorexics; BN, bulimics; EDNOS-AN, eating disorder nonotherwise specified-anorexic type; EDNOS-BN, eating disorder non otherwise specified-bulimic type; MeansGSD; BMI, body massindex; yrs, years; ms, months.

Pituitary–thyroid function and psychopathology in eating disorders 133

criteria from the study for both patients andcontrols were organic diseases, immunopathies,endocrinopathies (other than those related to ED),alcohol or drug abuse, organic brain disorders,cerebral trauma, and present or past Axis I or IIdisorders according to the DSM IV criteria (otherthan ED in the patients). Some of the patientspreviously received, very unsuccessfully, nutri-tional councelling, different types of psychothera-pies and pharmacotherapies with tricyclicantidepressants or Specific Serotonin ReuptakeInhibitors for short periods of time. However all ofthem were out of therapies at the time of ourobservation (since at least 6 weeks for pharma-cotherapies and longer time for psychotherapies).The demographic data of patients and controlsobtained when they entered the study are reportedin Table 1.

2.2. Psychological assessment

The day before blood drawing for PT hormoneassays, measures of psychopathological symptomswere obtained with the Eating Disorder Inventory-2(E.D.I.-2; Garner, 1991) and with the HopkinsSymptoms Cecklist (HSCL-90; Derogatis et al.,1974).

2.3. Thyroid activity

The neuroendocrine examination included assays ofTSH, FT4 and FT3.

Patients and controls arrived at the day hospitalof our institutes at 08:30 h for blood collection forhormone assays, after fasting the previous 12 h.Edetic acid anticoagulated blood was drawn,immediately centrifuged and the plasma frozen atK20 8C until assayed. The hormone assays weredone by immunofluorimetric methods (ELISA).Interassay coefficients of variations were 4.6% forTSH and FT3 and 8% for FT4; intraassay coefficients

of variations were 3.4% for TSH, 6% for FT4 and 5.7%for FT3.

2.4. Statistical analyses

Data were analyzed statistically by the nonparametric Mann–Whitney test to compare thehormonal values of patients and controls and bymultiple regression analysis (MRA) to test forcorrelations between hormonal and psychologicalparameters in patients. Since malnutrition isthought to be responsible for impaired HPT function(Spaulding et al., 1976; Leslie et al., 1978; Wakelinget al., 1979), we introduced in the MRA Body MassIndex (BMI) measurements as a covariate to controlfor the influence of the nutritional status of thepatients on the links between thyroid hormonefunction and psychopathology. Instead, since pre-vious psychotherapeutical or psychopharmacologi-cal treatments varied from patient to patient interms of type of therapy, their duration or efficacy,it was not possible to include them as covariates inour analyses.

3. Results

Hormonal data and their statistical significance arereported in Table 2. Differences between patientsand controls for concentrations of TSH, FT4 and FT3were observed, and were particularly frequent forFT3 values.

Results of multiple regression analyses, includingthe covariate BMI to exclude the effect ofmalnutrition on the correlations, revealed signifi-cant correlations between hormonal and psycho-pathological data. EDI-2 parameters revealed thatperfectionism correlated positively with FT4 in ANR(p!0.005, tZ2.29), ANP (p!0.05, tZ2.25), ANBP(p!0.002, tZ3.18) and with FT3 in ANBP (p!0.01,tZ3.5). Body dissatisfaction correlated negativelywith FT4 in ANP (p!0.006, tZK6.899). Sense of

Table 2 Pituitary–thyroid hormonal concentrations in eating disorder patients and in controls.

TSH (pg/ml) FT4 (pg/ml) FT3 (pg/ml)

ANR 1.9G1.5 3.3G0.7** 10.5G2.3†

ANP 1.3G1.0*** 3.3G0.7** 10.8G1.8§

ANBP 1.7G0.9 3.6G1.1** 10.3G1.5‡

BN 1.5G1.1§§ 4.8G0.6 9.8G3.2¶

EDNOS-AN 1.4G0.5§ 4.3G1.2 10.9G1.9¶¶

EDNOS-BN 2.2G0.7 5.0G0.8 10.9G1.6*CONTROLS 1.9G1.3 4.2G1.3 11.2G3.07

p!*0.05; **0.04; ***0.03; §0.02; §§0.01; ¶0.003; †0.002; ‡0.001.

F. Brambilla et al.134

ineffectiveness correlated positively with TSH inANR (p!0.05, tZK3.05) and negatively in BN(p!0.05, tZK3.05) and positively with FT3 inANR (p!0.02, tZ3.06) and ANP (p!0.02, tZ2.82).Interoceptive awareness correlated positively withFT4 in ANR (p!0.02, tZ4.11). Interpersonaldistrust correlated negatively with FT3 in ANR(p!0.04, tZK3.38). For the subitems of HSCL90, depression correlated negatively in ANR withTSH (p!0.04, tZK3.2), FT4 (p!0.005, tZK3.25)and FT3 (p!0.03, tZK3.67). Somatization corre-lated positively with FT3 in ANP (p!0.05, tZ3.05).Interpersonal sensibility correlated positively withFT3 in ANP (p!0.05, tZ2.25) Hostility correlatedpositively with FT3 in ANR (p!0.04, tZ2.07) andANP (p!0.01, tZ4.89). No other psychopathologi-cal parameters correlated with TSH, FT3, or FT4values.

4. Discussion

Even though our data are preliminary and will needto be confirmed by further investigations, theyseem to point out that the thyroid dysfunctions sooften observed in ED, and occurring in our patients,may be somehow correlated with specific psycho-pathological aspects of the disorders. These corre-lations do not necessarily mean a cause–effectrelationship, but rather hint that the two phenom-ena may to some extent depend one from the other.

Thyroid dysfunctions have always been thoughtto be nutritionally-induced. However, the linksbetween the psychological and PT impairmentsobserved in our patients did not seem to be due tothe altered nutrition occurring in AN and BNbecause, when BMI was introduced as a covariateof the hormonal effects on the psychopathologicalaspects of the diseases, the nutritional andendocrine factors dissociated from one another intheir correlations with ED psychopathology.Another observation that tends to rule out thatundernutrition is responsible for a PT-linked modu-lation of psychopathological impairments in AN and

BN, is that correlations between PT dysfunctionand psychopathology were also observed in theatypical forms of AN and BN (EDNOS-AN and BN)where nutrition was better preserved.

The fact that thyroid abnormalities have beenreported to disappear after full nutritional rehabi-litation in both AN and BN whereas some psycho-pathological aspects, especially perfectionism,have been reported to persist (Spaulding et al.,1976; Leslie et al., 1978; Tozzi et al., 2004) seems toexclude a cause–effect relationship between hormo-nal and psychological pathologies. This does notpreclude the possibility that altered thyroid functionmight modulate the consistency and the severity ofthe psychopathological aspects and their persist-ence after recovery or reappearance after relapse.To confirm or reject this suggestion our data willneed to be controlled in larger groups of patients bylongitudinal studies during the course of thediseases, after their recovery or chronicization orrelapses, and under different types of treatments.

The first hypothesis of our study was that thyroidimpairments could modulate depression in ED, as ithas been repeatedly reported to occur in endocri-nopathies and in Major Depressive Disorders (Baueret al., 2003; Larisch et al., 2004). But when weexamined our results, we observed an expectednegative correlation between TSH, FT4, FT 3 anddepression only in EDNOS-AN. Sense of ineffective-ness might be related to depressed mood, and itwas found to correlate negatively with TSH in BNand EDNOS-AN, and positively with FT3 in ANR, ANPand BN. Body dyssatisfaction too could be related todepression, and was observed to be linked to FT3 inEDNOS-BN.

The fact that thyroid alterations do not seem tocorrelate consistently and uniformly with most ofthe psychopathological aspects in all the EDpatients, independently of their subdiagnoses, isintriguing. Only FT4–FT3 values seem to correlatepositively with perfectionism across the entireproband group, which suggests that this specificpsychopathological aspect may be hormone-

Pituitary–thyroid function and psychopathology in eating disorders 135

dependent. When the correlations between FT4 andFT3 concentrations and perfectionism were studiedseparately in each patient subgroup, this link wassignificant for FT4 only in ANR and ANBP patients,and for FT3 in ANBP and BN patients. All together,however, our data suggest that a positive linkbetween FT4 and FT3 secretion and perfectionismmay exist. Since perfectionism might be anexpression of obsessivity–compulsivity and there-fore of an anxiety disorder, our data seem toconfirm the existence of a correlation between PTdysfunctions and anxiety in ED. Perfectionism isconsidered to be a genetically-related trait and nota state character, possibly preceding the onset ofthe diseases and persisting after their recovery(Tozzi et al., 2004), which seems to exclude thepossibility that changes in thyroid function mayinfluence the development and the course of thisspecific psychopathology. Yet, it cannot be fullyruled out that FT4 and FT3 may modulate theseverity of perfectionism.

That the concentration of each of the three PThormones correlated positively or negatively withone or another psychopathological aspect of ED inour patients (body dissatisfaction, interoceptiveawareness, interpersonal distrust, interpersonalsensibility, hostility, somatization) but not withall of them, and especially not across the entiregroup or subgroups of ED patients is intriguing,especially since the correlations occurred mostoften in the atypical forms of the disorders (EDNOS-AN and EDNOS-BN), while we would have expectedstronger correlations with the more severe EDpathologies. This could have been due to inter-ferences from the relatively small number ofpatients in each group, to the differences in theduration and severity of the syndromes, thedifferences in the previous histories of the disorders(treatments, hospitalizations, presence of severelife events, history of abuse, etc.) which we couldnot include as covariates in our analyses since theproband groups were generally too small. More-over, the different time of effectiveness of thethree hormones (short lasting for TSH and FT3 andlonger lasting for FT4 (Larsen et al., 1998) couldhave affected the stability of their influence on thedevelopment and persistence of the psychopathol-ogy of AN, BN, EDNOS-A and EDNOS-BN.

Our results are biased by two facts. First, thediagnostic subgroups do not include the samenumber of patients, some being relatively small,and the number of controls does not match that ofpatients, which could be considered a source oferror in the statistical analyses. Second, wemeasured hormonal and psychological parametersonly once, only at one time of day, and only in

the very acute phases of the disease, without takinginto account the circadian variations of the threehormones, the day-to-day fluctuations of thepsychopathologies and their course. As wementioned above, our study is only preliminaryand does not intend to state that altered thyroidfunction in ED is, by itself, responsible for some orall of the psychopathological symptoms of thediseases. What our data may suggest is that alteredthyroid function may modulate the severity,consistency and persistence of some psychologicalaspects and should, therefore, be taken intoconsideration in the therapeutic approaches to ED.

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