Psychological FactorsAffecting Physical Condition

Endocrine DiseaseLiterature Review

GALE BEARDSLEY, M.D.

MICHAEL G. GOLDSTEIN, M.D.

Research exploring the relationship between psychological factors and the onset,exacerbation, and perpetuation ofendocrine diseases has focused primarily on threediseases: diabetes mellitus (DM), Graves' disease, and Cushing's disease. There isinsufficient evidence to support the position that psychological factors directly affectthe onset ofDM. Recent laboratory studies suggest that stress is associated withchanges in glucose regulation in a subset ofdiabetic patients and that temperamentand coping strategies influence glycemic control in diabetic children and adolescents.Relaxation training may improve blood glucose control in non-insulin-dependent DMpatients. There is no good evidence that psychological characteristics affect the devel­opment and course of thyroid disorder or Cushing's disease. Recommendations aremade for future research.

I n this article, we review research that hasexplored the relationship between psycho­

logical factors and the onset, exacerbation, andperpetuation of endocrine diseases. Such re­search has focused primarily on three diseases;diabetes mellitus (OM), Graves' disease, andCushing's disease. The effects of psychologicalfactors on other endocrine disorders have re­ceived only scant attention. We will not reviewresearch within the emerging area of neuro-

Received August 27. 1990; revised August 4. 1992;accepted August 12. 1992. From the Butler Hospital. theDepartment of Psychiatry and Human Behavior. BrownUniversity School of Medicine. and the Division of Behav­ioral Medicine. Department of Psychiatry. The Miriam Hos­pital. Providence. RI. Address reprint requests to Dr.Goldstein. Dept. of Psychiatry. The Miriam Hospital. 164Summit Ave.• Providence. RI 02906.

Copyright Cl 1993 The Academy of PsychosomaticMedicine.

12

endocrinology here, although studies that focuson the physiology of the neuroendocrine re­sponse will undoubtedly shed light on the rela­tionships between psychological factors andneuroendocrine function. Also, we will not re­view the extensive literature on the relationshipbetween endocrine disorders and the develop­ment and exacerbation of psychiatric disordersand neuropsychiatric symptoms.

METHODS

Literature for this review was identified usingseveral strategies. We accumulated several per­tinent review articles and chapters as a result ofclinical work and research. References cited inthese review articles were obtained when rele­vant. In tum, relevant references cited in origi­nal studies were also obtained. To identify other

PSYCHOSOMATICS

Beardsley and Goldstein

a reliable interview instrument, informationwas gathered about the 3-year period precedingthe diagnosis of IODM. The diabetics had ahigher frequency (77%) of one or more severelife events prior to diagnosis compared withtheir disease-free siblings (39%) and age-/gen­der-matched controls (15%). There was also ahigher percentage of diabetics (54%) who hadtwo or more severe life events prior to diagnosiscompared with siblings (8%) and neighborhoodcontrols (8%). A recent Swedish study of over338 children with IODM and over 500 matchedcontrols found no difference between thesegroups in the total frequency !Jflife events in theyear prior to diagnosis.6 However, in children

age 5-9, events re­lated specifically toactual or threatenedlosses within thefamily were signifi­cantly more fre­quent in the diabeticchildren comparedwith controls (rela­tive risk = 1.82).The relative riskwas significantly in­creased even whencontrolled for age,gender, and socialstatus. This studysuggests that quali­tative characteris-tics of"stress," suchas the meaning of alife event or when it

occurs, may be more important than the fre­quency of life events in understanding the rela­tionship between stress and the onset ofdiabetes.

In contrast, other studies have found noevidence of a causal relationship betweenstressful life events and DM. Gendel andBenjamin7 studied hospitalized military pa­tients and found insufficient evidence to showthat stress had caused DM. In retrospectivestudies such as these, it is difficult to determinewhether a stressful event preceded the illness or

This article by Drs. Beardsley and Goldstein is thelast in a series of critical review articles that arebeing written as part of the process of examiningthe category "Psychological Factors AffectingPhysical Condition" for possible revisions inDSM-W. Emphasis in conducting these reviews isplacedon examining the existing scientific evidencefor relationships between psychological and be­havioral factors as influences on the onset. exacer­bation. and outcome of medical illness. Thisspecial series is edited by Alan Stoudemire. M.D .•who also is serving as the chair ofthe subcommitteeexamining PFAPC for DSM-W. As part of thisseries and the DSM-IV revision process. the editorswelcome the responses and suggestions of inter­ested readers.

RESULTS

Diabetes Mellitus: PsychologicalFactors Affecting Onset of Illness

review articles, we conducted a computerizedliterature search, using the MEDLINE database. Search terms included "psychological fac­tors," "endocrine," and the word stem "psych."The MEDLINE search was limited to Englishlanguage review articles from the last 5 years.

Several investigators have looked at therelationship between psychological factors andthe onset of DM. Thomas Willis I wrote thefollowing about DMin the 17th century:"Sadness, or longsorrow, as like con­vulsions, and otherdepressions and dis­orders of the animalspirits are used togenerate or fomentthis morbid dispo­sition." Maudsley,2Menninger,J andDunbar4 speculatedthat DM is causedby mental anxiety.However, early stu­dies that attemptedto show that acute orchronic stress is acause of DM are sig-nificantly flawedbecause of small numbers of subjects, inade­quate control groups, or poor experimental de­sign. Because of these flaws, their conclusionthat there is a causal relationship between stressand.the onset of DM is suspect.

More recently, a retrospective study gavesupport to the idea that stressful life eventscould become "triggering" factors in the eti­ology of insulin-dependent DM (IODM). Rob­inson and Fuller examined 13 newly diagnoseddiabetics, ages 17-34, as well as the diabetics'siblings and neighborhood controls. By use of

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Psychological Factors and Endocrine Disease

vice versa. However, a large prospective study8of air traffic controllers demonstrated noincreased risk of developing OM during a 2­year period. In this study, the air traffic con­trollers were matched to a group of men whowere functioning in jobs that did not requirerapid decision making and high levels ofresponsibility.

Our review of the available literature indi­cates that there is insufficient evidence to sup­port the position that psychological factorsdirectly affect the onset of OM. Additional pro­spective studies of patients at risk for diabeteswith larger numbers of subjects and with im­proved methodology are necessary before amore definitive statement can be made. In arecent review article, Helz and Templeton9 con­cluded that researchers have not been able todetermine whether psychological factors have acausal role or whether they are effects of theillness. The following section will discuss therelationship between psychological factors andthe course of DM.

Oiabetes Mellitus: PsychologicalFactors Affecting Course of Illness

Relationship Between Stress and the Course ofDiabetes. There have been several studies in­vestigating the relationship between psycholog­ical factors and metabolic control of glucose inpatients with DM. Investigators have hypoth­esized that psychological factors may affectmetabolic control directly by affecting neuroen­docrine target organs. However, psychologicalfactors can also affect compliance with recom­mendations about diet, activity, self-monitoringof glucose control, and medication.9 The resultsof studies that have not controlled for compli­ance must be interpreted with caution.

In addition, several early studies have othermethodological problems. Early measures ofglucose control, such as glucose and ketonelevels in urine and blood, episodes of ketoaci­dosis, insulin requirements, frequency of clinicvisits, and serum triglycerides and cholesterol,were relatively unreliable. More recently,glycosylated hemoglobin, a more reliable mea-

14

sure of metabolic control, has been used. Otherstudies1o-Is have been criticized for such meth­odological deficiencies as pooling 100M andnon-100M patients in the same study, using apopulation of highly selected patients, poor def­inition of experimental conditions, and failureto standardize the stressful situation used as theexperimental manipulation.

A study by Kemmer et al. 16 attempted toavoid these previous shortcomings in their ex­amination of the effects of acute stress on met­abolic control of glucose in 18 subjects. Threegroups-healthy controls, normoglycemic pa­tients with 100M, and hyperglycemic patientswith 100M-were matched according to age,weight, gender, and socioeconomic status. Eachsubject was subjected to two stressors: 45 min­utes of mental arithmetic and 5 minutes of pub­lic speaking. All subjects experienced similarincreases in heart rate, blood pressure, plasmaepinephrine levels, and plasma norepinephrinelevels. Plasma cortisol rose significantly afterpublic speaking in all groups. Neither stressorcaused significant changes in circulating levelsof glucose, ketones, free fatty acids, glucagon,or growth hormone in patients or controls. Theauthors concluded that sudden, short-lived psy­chological stresses are not likely to affect me­tabolic control in 100M even though theyproduce changes in cardiovascular responsesand moderate elevations in plasma catechola­mines and cortisol. Goetsch,17 in a recent reviewof studies that have examined the relationshipbetween acute laboratory-induced stress andblood glucose, provides further insight intomethodological problems associated with thistype of research.

Two recent studies have shown support forthe hypothesis that psychological stress is asso­ciated with changes in glucose control in at leasta subset of 100M patients. The research ofHalford et al. 18 and Gonder-Frederick et al. 19

both used within-subject design and analyticstrategies. Both groups found that some indi­viduals are more metabolically sensitive tostressors than others.

The work of Halford et al,,8 involved 15100M patients who self-monitored psycholog-

PSYCHOSOMATICS

ical stress, diet, exercise, insulin dose and bloodglucose levels over 8 weeks. At the beginningof the study, the subjects completed the HasslesScale and the Recent Life Changes Question­naire; glycosylated hemoglobin concentrationswere also calculated. There were no statisticallysignificant correlations between glycosylatedhemoglobin levels, daily hassles scores, and lifeevents scores. However, 7 of 15 subjects hadstatistically significant associations betweenmeasures of daily psychological stress andblood glucose levels.

Using a closed-loop insulin/glucose infu­sion system, Gonder-Frederick et al. 19 moni­tored continuous blood glucose as they exposed14 subjects with 100M to two 20-minute stan­dardized stressors and a control condition dur­ing two laboratory sessions 12 weeks apart. The"active" stressor involved doing mental arith­metic, the "passive" stressor was watching adisturbing drivers education film, and the con­trol condition was listening to a comedy recordalbum of the subject's choice. Gonder-Freder­ick et al. 19 found significant changes of greaterthan 17 mg/dl in the glucose levels of 8 of 14subjects when they were exposed to the activestressor during the first laboratory session. Sig­nificant changes in blood glucose levels werenot found during the second laboratory ses­sions, apparently reflecting the development ofhabituation. The passive stress and control con­ditions did not produce statistically significantchange in blood glucose levels during eithersession.

These findings contrast with those ofKemmer et al. 16 and most likely reflect dif­ferences in the study design. Although Halfordet al.18 and Gonder-Frederick et al. 19 reporteddata for individual subjects, Kemmer et al. 16

compared blood glucose values across subjects,time intervals, and stressor conditions. Thewithin-subject approach of Halford et al. 18 andGonder-Frederick,'9 despite relatively smallsample size, suggests that some individuals aremore vulnerable to the effects of stress thanothers. If this is true, it would be useful to learnmore about how respondents differ from non­respondents.

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Beardsley and Goldstein

Because stress is the psychological factormost often studied, it is important to note thatthere is a trade-off between studying the effectsof reliable laboratory stressors that are not veryapplicable to daily life (e.g., mental arithmeticand public speaking) and those stressors thatmay be more applicable but less reliable (e.g.,stress interviews, daily hassles). Also, the studyof the effects of acute stress in a laboratoryparadigm leaves the question of the effects ofchronic stress unanswered.

Lloyd et al.20 recently published the resultsof a prospective study of 130 adult 100M andnon-100M patients. The presence of severe lifeevents and difficulties was not significantly as­sociated with premature death or the develop­ment of macrovascular disease over the 4 yearsof follow-up. However, those who began anti­hypertensive therapy during the follow-up pe­riod were significantly more likely to haveexperienced five or more severe life events dur­ing the previous 5 years than those who did notbegin antihypertensive therapy. This relation­ship was not mediated by baseline blood pres­sure, type of diabetes, gender, or ethnicity.Clearly, more prospective studies are needed toassess the effects ofchronic stress on the courseof diabetes.

Relationship Between Personality and CopingStrategies and the Course ofDiabetes. Rovetand Ehrlich21 addressed the issue of tempera­ment or personality and its possible effect onmetabolic control in children with 100M. Twostandardized temperament questionnaires werecompleted by parents of51 children with 100Mand 24 healthy control subjects. First, they ob­served no difference in temperament betweendiabetic children and sibling control subjects.There also was no unique diabetic temperamentprofile. However, using glycosylated hemoglo­bin as an outcome measure of metabolic con­trol, they observed an effect of temperament onglycemic control. Oiabetic children who weremore active, were better at following routines,displayed milder responses to external stimuli,were less attentive, and were more prone tonegative moods had improved metabolic con-

\S

Psychological Factors and Endocrine Disease

trol when compared with the other diabeticchildren. The authors avoided implying acause/effect relationship. Because child and ad­olescent subjects may show marked variation inemotional maturity, in the extent of parentalinvolvement and supervision, and in residualpancreatic ability to secrete insulin, these re­sults cannot be generalized to other age groups.However, the study by Rovet and Ehrlich21

demonstrates the utility of developing methodsof evaluation that are specific for the agegroup's psychological and medical characteris­tics.

A study by Stabler et al. 22 also investigatedthe relationship between personality traits andglucose regulation in a psychophysiologicstudy of diabetic children. Children with type Abehavior, identified from their responses tovideo games, had a hyperglycemic response tostress that was not present in children with atype B behavior pattern. In a study investigatingthe relationship between coping behavior andglucose control in adolescent diabetics,Oelamater et al. 23 found that those in poor con­trol used significantly more wishful thinkingand avoidance than those in better control. Han­son et al. 24 found that the effects of stress onmetabolic control in diabetic adolescents wasbuffered in subjects scoring high on measuresof social competence; those with low socialcompetence had marked worsening of meta­bolic control (as reflected in glycosylated he­moglobin) in response to stressful life events,and those with high social competence scoresdemonstrated minimal changes in metaboliccontrol. Kuttner et al. 2S found the "learned help­lessness" attributional style for negative eventswas significantly associated with glycosylatedhemoglobin in a group of 50 diabetic children(ages 10-16). Learned helplessness was not as­sociated with regimen adherence. Hanson etal.24 and Aikens et al.,26 also found that stresshad an effect on metabolic control that wasindependent of its effect on compliance.

Relationship Between Psychosocial Interven­tions and the Course of Diabetes. Severalstudies have reported the effects of behavioral

16

or psychosocial interventions on glucose con­trol in diabetic patients. Surwit and Feinglos27

and Lammers et al.28 found that relaxation train­ing can improve blood glucose control in non­100M diabetics. However, relaxation traininghas not produced consistent benefits in 100Mpatients.29 Surwit and FeinglosJO have specu­lated that stress may be of more importance inblood glucose fluctuations in non-100M thanin 100M patients. In their review, Helz andTempleton9 describe several anecdotal reportsthat suggest that individual or family psycho­therapy may improve diabetic control in somepatients, but there are no controlled studies thatdemonstrate the efficacy of these interventionsin enhancing diabetic control.

Summary: Relationship Between PsychosocialFactors and the Course of Diabetes. In sum­mary, although retrospective studies suggest arelationship between stressful life events andthe course of OM, these studies are method­ologically flawed. A well-controlled studyl6 ofthe effects of laboratory-induced stress on mea­sures of glycemic control found there was noeffect in both patients with OM and controls.However, recent laboratory studies,18.19 usingwithin-subject designs, suggest that stress isassociated with changes in glucose regulationin a subset ofdiabetic patients. One prospectivestudy20 has reported a relationship betweenstressful life events and the need for antihyper­tensive therapy. There is also some evidence tosuggest that temperament and coping strategiesinfluence glycemic control in child and adoles­cent diabetics.21-2s Relaxation training may im­prove blood glucose control in non-100Mpatients,27.28 but there is no consistent benefit in100M patients.29

RESULTS: GRAVES' DISEASE

Since the first description of Graves' disease,otherwise known as exophthalmic goiter, clini­cians have suspected that psychological andsocial factors contribute to its etiology andcourse.31 Graves' disease was one of the "holyseven" psychosomatic disorders studied by Al-

PSYCHOSOMATICS

exander and described in his famous treatise,Psychosomatic Medicine. 32 Weiner's31 com­prehensive and scholarly review of Alexander'swork, as well as the work of more recent inves­tigators who have studied the effects of psycho­logical factors on Graves' disease, provide thebasis for the discussion that follows.

It should be noted that almost all of theresearch studies that Weiner reviewed had seri­ous methodological flaws, including retrospec­tive or cross-sectional design, poorly definedpatient populations, and lack of appropriatecontrol groupS.31 Also, the highly variable onsetand course of Graves' disease makes it difficultto attribute changes in course to psychologicaland behavioral factors. 31 Moreover, the hyper­thyroid state that usually accompanies Graves'disease is itself characterized by a host of psy­chological, behavioral, and neuropsychiatricsigns and symptoms.33-3S Because the earlystages of Graves' diseases may develop slowly,psychological and behavioral factors that ap­pear to precede illness activity may actually beconsequences of unrecognized changes in thy­roid function.3\ Weiner concludes from his ex­tensive review of the literature that there is noevidence to suggest that psychological charac­teristics of patients predispose them to developGraves' disease, or any other thyroid disorder. 31

Recently, however, a population-based,case-controlled study was published that sug­gests negative life events may be risk factors forGraves' disease.36 Over 2 years, 95% of 219eligible patients with newly diagnosed Graves'disease and 372 matched controls answered anidentical mailed questionnaire assessing demo­graphic variables, life events, social support,and personality. Compared with control sub­jects, Graves' patients had more negative lifeevents in the 12 months preceding the diag­nosis; negative life-event scores were also sig­nificantly higher (odds ratio =6.3) for thecategory with the highest negative score. Also,these investigators found that slightly more pa­tients than control subjects were divorced.These results were independent of other possi­ble confounding risk factors. Prospective stud­ies are needed to confirm these findings. There

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Beardsley and Goldstein

is presently insufficient evidence to suggest thatpsychological factors affect the course ofGraves' disease.

RESULTS: CUSHING'S DISEASE

Gifford and Gunderson37 reviewed the literatureon the relationship between psychological fac­tors and Cushing's disease and described 10cases. They hypothesize that Cushing's diseaserepresents a pathophysiological reaction to be­reavement in predisposed individuals. Cushingargued that emotional stress contributed to thedevelopment of the disease that bears his name.He is quoted in Gifford and Gunderson's re­view: "Within normal physiological limits indi­viduals differ greatly ... in the character anddegree of their secretory response under theinfluence of primitive emotions," and "underspecial psychic durance [these responses] mayacquire a sufficient chronicity to lead to a so­called symptom-complex of disease.'037 How­ever, most of the nonanimal studies that Giffordand Gunderson cite are retrospective, and nocontrolled studies in humans have been done, toour knowledge, that would either support orreject their hypothesis. Although stressful stim­uli may acutely lead to increased secretion ofcorticosteroids, hypercortisolism cannot beequated with illness and disease. Moreover,hypercortisolism of several etiologies, includ­ing Cushing's disease, have been associatedwith the development of a wide range of neuro­psychiatric phenomena.33 Thus, as Cushing alsostated, there is "difficulty in determining whichwas the primary factor-the psychic instabilityor the disturbance of endocrine secretion."37

CONCLUSIONS ANDRECOMMENDAnONS FOR

FURTHER RESEARCH

There is a paucity of research on psychologicalfactors affecting endocrine disorders, espe­cially when considering endocrine disordersother than DM. Most of the studies that wesurveyed were quite dated and had either aretrospective design or other serious meth-

17

Psychological Factors and Endocrine Disease

odological flaws. OM appears to be the onlyendocrine disorder that has been the focus ofrecent research studies that are significantlyimproved in design. However, there have beenno consistent results demonstrating that psy­chological factors affect the onset of OM. Onlya small number of studies have demonstratedthat psychological factors affect the course ofdiabetes, and most of these have reported theeffects of acute stressors on measures of glu­cose control.

Several recommendations can be made forfuture research in this area. The methodology ofstudies in this area would be enhanced by pro­spective designs, well-defined subject popula­tions, and meaningful control groups. There isa need to identify age-specific issues that mightaffect outcome (e.g., children and adolescentswith OM may react differently to a givenstressor than adults). The use of better methodsto measure long-term glycemic control (e.g.,glycosylated hemoglobin) should help to assess

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6. Hagglof B. Blom L. Dahlquist G. et a1: The Swedishchildhood diabetes study: indications of severe psycho­logical stress as a risk factor for type I (insulin-depen­dent) diabetes mellitus in childhood. Diabetologia 1991;34:579--83

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9. Helz JW. Templeton B: Evidence of the role of psy­chosocial factors in diabetes mellitus: a review. Am JPsychiatry 1990; 147:1275-1282

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t8

the relationship between psychological factorsand the course of OM. Laboratory paradigms toassess the physiological reactivity of the endo­crine system to psychological challengesshould be used and developed. These paradigmsmight help to elucidate further the psychophys­iologic mechanisms that may underlie the rela­tionships between psychological factors andendocrine disease.

Psychological factors that have the mostclinical relevance, such as anxiety and depres­sion, should be investigated in prospective stud­ies ofpatients with endocrine diseases. Creativeways to assess the impact of real-life stressorson endocrine function are also needed. Compli­ance with all aspects of the treatment/experi­mental intervention plan should always bemonitored with both experimental and controlsubjects. Finally, there is an obvious need forwell-designed research to study the effects ofpsychological factors on endocrine diseasesother than OM.

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stress and blood glucose regulation in type I diabeticpatients. Health Psycholl990; 9:516-528

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22. Stabler B, Surwit RS, Lane ro, et a1: Type A behaviorpattern and blood glucose control in diabetic children.Psychosom Med 1987; 49:313-316

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