obesity and cortisol

INGESTIVE BEHAVIOR AND OBESITY

Obesity and CortisolPer Bjorntorp, MD, PhD, and Roland Rosmond, MD, PhD

From the Department of Heart and Lung Diseases, Sahlgrens Hospital, University ofGoteborg, Goteborg, Sweden; and the Pennington Biomedical Research Center, Louisiana

State University, Baton Rouge, Louisiana, USACortisol in obesity is a much-studied problem. Previous information indicates that cortisol secretion iselevated but that circulatory concentrations are normal or low, suggesting that peripheral disappearancerate is elevated. These studies have usually not taken into account the difference between central andperipheral types of obesity. Recent studies using saliva cortisol have indicated that the problem is complexwith both high and low secretion of cortisol, perhaps depending on the status of the function of thehypothalamicpituitaryadrenal gland axis. A significant background factor seems to be environmentalstress. The results also suggest that the pattern of cortisol secretion may be important. Other neuroen-docrine pathways are also involved, including the central sympathetic nervous system, the gonadal andgrowth hormone axes, and the leptin system. In concert, these abnormalities seem to be responsible forthe abnormal metabolism often seen in central obesity. Several associated polymorphisms of candidategenes may provide a genetic background. Cortisol conversion to inactive metabolites may be a factorincreasing central signals to secretion and may add to the increased secretion of cortisol induced bycentrally acting factors. Perinatal factors have been found to be involved in the pathogenesis of obesityand its complications. The mechanism involved is not known, but available information suggests thatprogramming of the hypothalamicpituitaryadrenal axis may be responsible. Nutrition 2000;16:924936. Elsevier Science Inc. 2000

Key words: obesity, cortisol, sympathetic nervous system, sex steroid hormones, growth hormone,perinatal factors

INTRODUCTION

Certain cases of obesity have clear clinical features of hypercor-tisolism, including a central fat distribution of excess body-fatmass, sometimes with a tendency to a Buffalo hump, elevatedblood pressure, insulin resistance with impaired glucose tolerance,and dyslipidemia. This has led many researchers to investigate thepossibility of whether human obesity is in fact a hypercortisolemiccondition. Since the beginning of the Medline register in 1966, nofewer than 730 publications have been found under the combinedsearch words cortisol and obesity, amounting to 294 during thepast decade. These numbers by themselves indicate both the pro-found interest and importance of the subject and that a consensuson potential abnormalities does not exist.

Therefore, we have attempted to review the literature andcompare previous and more recent results with methods that seemmore adequate than those used previously for the examination ofthis complex problem. As apparent from the large numbers ofpublications, all cannot be included. Therefore, the ambition hasbeen to select publications that seem particularly informative byusing sound methodology on a reasonable number of subjects.Animal work has been excluded because the relevance of animalmodels for human obesity is uncertain. Only when mechanisticstudies are referred to, difficult or impossible to perform in hu-mans, has animal work been cited.

BACKGROUND

The reason for most studies of cortisol secretion in human obesityhas probably been the similarities between hypercortisolemicstates and certain patients with obesity. Another probable reason isthat several animal models of obesity have been characterized byincreased secretion of glucocorticoids. This is the case with theob/ob mouse, and the syndrome can be in essence reversed byadrenalectomy.1 Another well-known rodent model, the Zuckerrat, shows similar characteristics.2 It seems doubtful, however, thatthe elevated level of corticosterone is solely responsible for theobesity because administration of this hormone does not causesuch severe obesity as in the rat models mentioned, suggesting thatother factors are also involved.

A human counterpart to these syndromes in rodents is notevident. However, as will be discussed, human obesity seems to befollowed by several signs of hypothalamic dysfunctions, similar tothose in the rodent models, but usually to a lesser degree. Aconcerted action of such abnormalities may provide a pathogeneticbackground for human obesity, as will be suggested in thisoverview.

An important question, however, is whether these abnormali-ties are primary causes of obesity or consequences of the obesestate. Critical experiments to test this possibility should examinewhether the hypothalamic abnormalities precede the obese state orremain after reduction of the excess body fat mass to normallevels. The first alternative is, for obvious reasons, difficult to testand does not seem to have been performed. The problem with thesecond alternative is that reduction from a certain excess bodyweight by diminution of body fat stores is followed by secondaryneuroendocrine adjustments that strive to reestablish the non-reduced body weight. This reduced condition is similar to starva-tion irrespective of remaining available body fat mass3 and isprobably from unknown regulatory mechanisms that are dependenton a steady-state setpoint established in the condition before re-

Correspondence to: Per Bjorntorp, Department of Heart and Lung Dis-eases, Sahlgrens Hospital, University of Goteborg, Goteborg 413 45,Sweden. E-mail: [email protected] accepted: June 23, 2000.

Nutrition 16:924936, 2000 0899-9007/00/$20.00Elsevier Science Inc., 2000. Printed in the United States. All rights reserved. PII S0899-9007(00)00422-6

duction of body fat. Unfortunately, this seems to make tests of aprimary hypothalamic aberrations in human obesity by analysesafter weight reduction cumbersome, and any remaining aberra-tions would be blurred by the starvationlike counterregulatorymechanisms.

The Vermont overfeeding experiments in humans are informa-tive with regard to the question of whether elevated cortisolsecretion is primary or secondary in human obesity. When youngmen ate to increase body fat mass, cortisol production rates and17-OH corticosteroid excretion were increased,4 indicating thatslight to moderate obesity induced by overnutrition is followed byelevated cortisol secretion. There is, however, an important dis-tinction between obesity created by force feeding and that occur-ring spontaneously. Evidence suggests that in spontaneous obesitythe restriction of energy intake is followed by elevated cortisolsecretion5; in other words, a situation opposite to that of forcefeeding is also followed by elevated cortisol levels. In both situ-ations, endogenous mechanisms seem to maintain a certain bodyfat mass and keep a given setpoint. Such counterregulatory mech-anisms (allostasis) are frequently driven by the hypothalamicpituitaryadrenal (HPA) axis.6 Therefore, in starvation and itsequivalent, voluntary body-weight reduction or prevention ofspontaneous body-weight increase, and in overfeeding, activationof the HPA axis and elevated cortisol secretion may be secondaryphenomena.

Cortisol secretion has been examined extensively in relation tohuman obesity. When abnormalities have been observed, evidencesuggests that these are mainly because of abnormal regulation ofthe HPA axis, although there is also evidence that peripheralmodulations result in cortisol exposure of tissues. In addition,several other hypothalamic abnormalities have been reported inhuman obesity. Taken together, these results indicate that theregulation of the neuroendocrine and autonomic nervous systemsare involved in a broader sense.

REGULATION OF THE HPA AXIS

Cortisol secretion is regulated by hypothalamic centers that receivestimulatory signals from the central nervous system. These signalsare modified by adrenergic, dopaminergic, and serotoninergic sys-tems and other central factors in a complicated system that is onlypartly understood.7 The regulatory, central events result in a char-acteristic diurnal profile of cortisol secretion with high activity inthe early morning hours and low activity in the afternoon andevening. Superimposed on this basic, physiologic regulation, thecentral signals are dependent on the registration and perception ofnumerous environmental factors and are registered and integratedinto appropriate peripheral signals through hypothalamic centers.This has the purpose of maintaining homeostasis in several regu-latory systems.

The HPA axis has a central role in these events. Several ofthese regulatory systems allow a certain amplitude of variation(allostasis),6 e.g., blood-pressure regulation in different postures orinsulin secretion with food intake. The primary signals to thecentral nervous system are delivered by the senses or by internalevents and are, particularly in humans, modified by experience,mood, and intellect. Factors that are received and modified throughthis complex regulatory system may be mentally perceived alter-ations or perceived changes in environmental temperature, noise,alcohol, smoking, drugs, and food intake. Examples of internalchanges are fever and other reactions to disease and pain. Moodchanges are involved, ranging from feeling happy, miserable, oraggressive to psychiatric equivalents, or clinically established mel-ancholic depression or panic disorder.

A recent study has shown the impressive sensitivity of thisregulatory system in normal subjects.8 Cortisol was measured insaliva because saliva can be collected under any circumstances,except during sleep. These subjects delivered saliva on six differ-

ent occasions over an ordinary working day, determined by signalsfrom a clock, preset at random time points during the day. Thesesubjects reported perceived mood changes during the hours pre-ceding saliva delivery. They also reported that the conditions of thestudy and previously experienced or anticipated events influencedcortisol secretion. In addition, mood and affect in both positive andnegative directions affected cortisol levels. The results showed adoseresponse curve between the registered variables and cor-tisol concentration in saliva, with a variation amplitude of about20-fold.8

These factors are usually collected under the denomination ofstress. This is a convenient label but often misleading because it isusually considered in everyday conversations to mean anxious ingeneral, under time pressure, or having too much to do. Inscientific terms, stress consists of a large variety of factors fol-lowed by activation of hypothalamic centers. In fact, some stressresearchers avoid definition of external or internal stress factorsbecause of its complexity and examine the problem with biologicalvariables, i.e., the arousal of the HPA axis, in particular, and theautonomic nervous systems. These are the defense or defeatreactions in animal experiments, where the former causes chal-lenges of primarily the sympathetic nervous system and the latterthe HPA axis.9 In humans, these reaction types are difficult toseparate and are often mixed, although developing a profile ispossible.10 Although complex, the advantage of the term stress isthat it is generally understood to mean unpleasant strain and istherefore useful in questionnaires.

The HPA axis is controlled by a feedback regulatory systemthat sensitively regulates cortisol secretion to avoid excess periph-eral cortisol concentrations in the circulation, which will, particu-larly in the long run, cause unwanted effects. This control isexerted by glucocorticoid receptors (GRs) localized to differentregions of the brain, where those of the hippocampus area are ofparticular importance.6

Activity of the HPA Axis in Human ObesityNumerous studies have examined the urinary output of 17-ketogenic steroids (metabolites of cortisol), Porter-Silber chromo-genes, and cortisol. The kidneys secrete free cortisol; therefore,urinary cortisol measurements will provide an estimation of aver-age free, circulating diurnal cortisol concentrations. Several stud-ies have reported elevated cortisol output in obesity.1125 However,these studies do not take into account the fact that obese subjectshave an increased body mass, surface area, and often lean bodymass. Corrections have been performed in some of these studiesfor body surface area or creatinine output, the latter as an estima-tion of lean body mass, and cortisol output has then been foundto be elevated in some studies1719 but not in others.11,17,26,27Cortisol-binding globulin does not seem to be affected.28,29

More detailed studies of cortisol secretion rate, generally usingtracer turnover techniques, have also yielded different results de-pending on the basis of expression of data. In congruence withincreased urinary output of cortisol or its metabolites, an increasedcortisol production has been registered.16,23,30,31 Nevertheless, se-rum cortisol concentrations have not been found to be elevated;rather, normal or even low levels have been found in studiesreporting an increased urinary output.29,32 The rate of removal ofcortisol from the circulation has been reported to be elevated.33

Taken together, these reports indicate that cortisol secretion iselevated in the steady state in obesity and that removal is increasedto the degree that normal or even lower-than-normal circulatinglevels are maintained.

However, the crucial question seems to be, To what extent isthe obese organism exposed to elevated concentrations of cortisol?The answer is important in evaluating a peripheral hypercorti-solism in terms of reactions of peripheral organs. It seems reason-able to suggest that, with the elevated production of cortisol, the

Nutrition Volume 16, Number 10, 2000 925HPA Axis in Obesity

periphery would be exposed to higher-than-normal cortisol levelsirrespective of body size, surface area, or creatinine excretion.

Cortisol is secreted from the adrenal glands and then circulatesuntil it is taken up in other tissues. This uptake occurs by anapparently passive diffusion through the cell wall and then bindingto GRs, which are localized in both the cytoplasm and the nuclei.34The major effects of cortisol are then exerted by binding thehormonereceptor complex to glucocorticoid-responsive elementsof different genes, thereby initiating transcription and subsequenttranslation of active proteins. Cytoplasmic cortisol is, however,exposed to intracellular metabolism, which modifies the net, finalactive concentration, and effects. This is an additional mechanismdetermining peripheral exposure of cortisol (see later section onCortisol Metabolism).

Central and Peripheral Obesity

The studies mentioned above usually were performed on obesesubjects without considering either the subgrouping according tobody-fat distribution or the response of the HPA axis to differentchallenges. Although several of these studies were performedbefore the realization of the importance of distintinguishing be-tween central, abdominal, or visceral obesity, on the one hand, andperipheral or gluteofemoral obesity, on the other, one may haveexpected that clinicians would have been struck by the Cushin-goid appearance of the central-obesity type and directed exami-nations toward this subtype. Fairly recently, abdominal obesity hasbeen associated with risk predictors for diabetes type 2, cardio-vascular disease, and stroke (insulin resistance, dyslipidemia, andhypertension) and has been shown to be a risk factor for thesediseases, independent not only of obesity in terms of elevated bodyfat mass irrespective of localization but also of the other riskfactors. These associations are considerably less pronounced oreven absent in moderate peripheral obesity (for review, see Bjorn-torp35). In fact, in some of the studies on cortisol secretion inobesity, they excluded obese subjects with diabetes or hyperten-sion,36,37 and these patients presumably had a high prevalence ofcentral obesity. This kind of cohort might be expected to have beenfollowed by a selection of subjects with the peripheral type ofobesity.

More recent studies have taken this factor into account andhave found that dysregulation of the HPA axis with hypercortisol-emia seems to be more pronounced and prevalent in the centraltype of obesity in both men and women.3843 This may have beenone reason for the inconsistent findings where mixed groups ofobese subjects were studied.

Available evidence suggests that the stimulated HPA axisshows abnormalities in obesity more clearly than measurements ofbasal activity, particularly in central obesity. Such stimulationsinclude food intake,41,49 perceived stress, and direct stimulationwith corticotropin-releasing hormone or adrenocorticotropin. Ad-renocorticotropin tests have shown increased cortisol responses inabdominal-obese subjects,38,39,45 but these tests examined respon-siveness rather than sensitivity of the system and are thereforeless relevant for the everyday challenges of the HPA axis.Corticotropin-releasing hormone challenges have shown increasedresponsiveness in central-obese women39 but not in obesity ingeneral45 and not in obese men46 (unpublished results).

Submaximal stimulation of the HPA axis is more relevant inrelation to everyday situations. Mental and physiologic laboratorystress tests in both men and women with central obesity haveshown elevated cortisol responses.38,40,4749 In addition, whenstudied on a population basis, cortisol secretion frequently showselevated levels in response to reported, perceived stress, which isalso associated with centralization of body fat masses and signs ofthe metabolic syndrome (insulin resistance, dyslipidemia, andhypertension).42 This will be discussed in more detail in a follow-ing section.

Furthermore, response to food has been reported to be followed

by a larger cortisol response in central-obese than in controlsubjects and showed stronger associations than basal cortisol se-cretion to somatic symptoms.41

The feedback control of the HPA axis, as tested with thedexamethasone-suppression test, has been found to be normalwhen using the conventional dose of 1 mg, used for the diagnosisof severe hypercortisolemic states such as Cushings syndromeand melancholic depression.30,38 Lower doses of dexamethasoneappear to be more discriminative in the diagnosis of subtle abnor-malities of the feedback mechanism50 and show a mildly decreasedsensitivity of the inhibitory power, particularly in centralobesity.42,51

RECENT STUDIES USING A DIFFERENT APPROACH TOTHE PROBLEM

The studies reviewed in the preceding sections were performed onobese populations in comparisons with controls. Often conven-tional methods have been used, designed mainly for diagnosis ofsevere hypercortisolemic states such as Cushings syndrome. Itseems possible that such methods are not sensitive and discrimi-nating enough to allow detection of mild functional problems inthe regulation of the HPA axis. Furthermore, obesity is a slowlydeveloping disease and potential involvement of HPA-axis abnor-malities would be expected to be minor or changing. Such subtleperturbations would have to act during everyday conditions duringa prolonged period of time and requires sensitive techniques.

A different approach to this problem is to study the function ofthe HPA axis on a population basis and search for associationswith obesity and related phenomena. In addition, if regulatoryerrors are to be looked for, the kinetics of the regulation of theHPA axis should be studied, not only during basal conditions butalso during the influence of ordinary daily challenges such as foodintake and perceived stress. For this purpose, measurements ofsaliva cortisol seem ideal because saliva can be collected underany circumstances except during sleep. Saliva contains the free,active fraction of circulating cortisol and is independent of salivaflow. Although lower than circulating cortisol levels, excellentcorrelations between saliva and serum cortisol levels have beenfound50 (unpublished observations). Furthermore, by allowingself-delivery of samples for cortisol measurements, confounders ofHPA-axis regulation in the form of an unfamiliar milieu of ahospital or a laboratory can be avoided and venous punctures madeunnecessary; both are apt to disturb everyday regulatory patternsof the HPA axis. Such recent studies will be described in somedetail later in this review and attempts made to interpret the results,in particular in relation to obesity subgrouping and associatedendocrine, metabolic, and hemodynamic complications.

The methods used and the statistical treatment of the data havebeen published.41,42A subdivision in high and low variability of thecortisol day curve was performed, which allowed examinations ofthe input of perceived stress on cortisol secretion on the basis of anormal (high variability) and pathologic (low variability) regula-tion of the HPA axis. These results are shown in Table I andgraphically in Figure 1. Men with normal diurnal curves and highstress-related cortisol showed, in comparison with men with lowstress-related cortisol, lower values in the morning (P 5 0.003),and about three times higher values before and after lunch (P ,0.001), but no difference at bedtime. Total cortisol secretion,shown as an average of seven values over the day, was higher (P 50.004).

Men with a pathologic diurnal curve with low variability (lowercurve in Fig. 1) showed essentially similar high or low stress-related cortisol and were therefore not subdivided according toperceived stress. These men showed about 75% of total cortisolsecretion in comparison with the men with high variability and lowstress-related cortisol (P , 0.001), depending mainly on lower

926 Bjorntorp and Rosmond Nutrition Volume 16, Number 10, 2000

morning values (P , 0.001) and, to some extent, during lunch(P , 0.05).

It is thus apparent that the higher total cortisol secretion in themen with normal HPA-axis regulation (high variability) who weresensitive to perceived stress (high stress-related cortisol) is mainlyfrom a failure of decreasing morning cortisol levels before lunchand to higher lunch cortisol levels. The lower cortisol levels of themen with a pathologic regulation of the HPA axis (low variability)are caused mainly by lower cortisol levels in the morning, and, tosome extent, during lunch.

In summary, this analysis of saliva cortisol over the day showeddifferences not only in secretion pattern (high and low variability),mainly from differences in morning cortisol levels, but also instress sensitivity, reflected in about one-third of the men mainly asa failure of winding down cortisol values before lunch, and asensitivity to the physiologic challenge of the HPA axis by feed-ing. Approximately 10% showed a pathologic basal HPA-axisregulation. The day of examination was an ordinary working day,chosen at random, and the measurements are presumed to berepresentative for the typical diurnal cortisol secretion of theindividual in question.

RELATION BETWEEN HPA-AXIS ACTIVITY ANDOBESITY AND ASSOCIATED VARIABLES

The characteristics of HPA-axis activity were compared with mea-surements of obesity variables (body mass index, BMI; waist-to-hip circumference ratio, WHR; and sagittal abdominal diameter, asurrogate measurement of visceral fat mass),52 other endocrinefactors (testosterone and insulinlike growth factor-I, a surrogatemeasurement of growth hormone secretion), metabolic variables(fasting glucose, insulin, triacylglycerol, and total, low-, and high-density lipoprotein, cholesterol), and hemodynamic variables (sys-tolic and diastolic blood pressures and heart rate). Three groupswere examined: men with a normal diurnal curve (high cortisolvariability), and low stress-related cortisol, representing a normalgroup with a relatively minor influence of stress; men with anormal diurnal curve (high cortisol variability), representing anormally regulated HPA axis but with a relative sensitivity toperceived stress; and men with a pathologically regulated HPAaxis seen as a low variability. The cortisol measurements analyzedwere total cortisol secretion, representing basal, nonstimulatedcortisol secretion, and cortisol secretion stimulated either by lunchor by perceived stress, i.e., stress-related cortisol secretion. Thesecalculations of associations with the somatic variables were per-formed as correlation analyses. The results are presented in TableII.41,42

The men with a normal HPA-axis function, reporting littlestress, were considered the normal control group. They showednegative relations between total cortisol and BMI, WHR, andblood pressure. With the lunch values, this relation was also foundfor sagittal abdominal diameter, insulin, triacylglycerols, and heartrate. The results indicate that nonstimulated, basal cortisol secreted

TABLE I.

SALIVA CORTISOL VALUES (nmol/L) AT INDICATED TIMES IN218 MIDDLE-AGED MEN IN RELATION TO HIGH AND LOWVARIABILITY OF SALIVA CORTISOL VALUES OVER A DAY

High variability*(n 5 198, 90%)

Lowvariability

(n 5 20, 10%)

Lowstress-related

cortisol P

Highstress-related

cortisol P

n (%) 121 (61) 77 (39)Morning 21.8 (8.7) 0.003 18.4 (6.5) ,0.001 10.3 (4.8)Before lunch 6.3 (2.8) ,0.001 16.8 (18.5) NS 5.8 (2.1)Lunch 6.7 (3.4) ,0.001 19.7 (20.8) ,0.05 5.8 (2.0)Bedtime 3.7 (3.7) NS 3.6 (4.0) NS 3.2 (2.6)Average of all

values8.2 (2.6) 0.004 9.2 (2.2) ,0.001 6.1 (1.6)

* The high-variability group was divided into high and low stress-relatedcortisol-secreting groups (unpublished observations).41,42 Sum of values 30, 45, and 60 min after a standardized lunch. Comparisons with high variability and low stress-related cortisol level.NS, not significant.

FIG. 1. Saliva cortisol secretion in men.

TABLE II.

CORRELATIONS BETWEEN SALIVA CORTISOL VALUES(TOTAL OVER THE DAY, AFTER LUNCH, AND STRESS-RELATED CORTISOL) AND LISTED VARIABLES IN MEN

WITH HIGH OR LOW VARIABILITY OF DAY CURVEMEASUREMENTS (r-values)41,42

High variability Low variability

Total Lunch Stress Total Lunch Stress

BMI 20.13* 20.24 0.07 0.01 0.26 0.34WHR 20.16* 20.36 20.01 20.13* 0.19 0.45D 20.11 20.30 0.18 0.01 0.28 0.47T 0.24 20.18IGF-I 0.06 20.33Glucose 20.09 0.26 0.12* 20.02 0.27 0.43Insulin 0.02 20.17 0.11* 20.19 0.33 0.39Triacylglycerol 20.04 20.23 20.20 20.25 0.49 0.18Cholesterol

Total 0.22 0.35LDL 0.34 0.37HDL 0.04 20.24

SBP 20.29 20.28 0.09 0.20 0.72 0.31DBP 20.29 20.20 0.30 0.19 0.73 0.39Heart rate 0.04 20.24 0.00 0.14 0.48 0.31

* P , 0.05. P , 0.01. P , 0.001.BMI, body mass index; D, sagittal diameter; DBP, diastolic blood pres-sure; HDL, high-density lipoprotein; IGF-I, insulin-like growth factor-I;LDL, low-density lipoprotein; SBP, systolic blood pressure; T, testoster-one; WHR, waist-to-hip ratio.


in a normal diurnal pattern and in particular cortisol secretion afterthe physiologic stimulus of food intake were in these men associ-ated with a healthy profile across several variables.

It seems surprising that high cortisol values within this group ofmen would be associated with, e.g., low insulin values with thewell-known effects of cortisol to induce insulin resistance. Themen with a high plasticity of HPA-axis regulation and a low stresssensitivity presumably represent a normal regulatory system, withlimited effects by the external pressure of stress. The diurnal, totalcortisol secretion in this group of men is dependent mainly on thehigh cortisol values in the morning, which are particularly indic-ative of a normal regulation of the HPA axis, which is physiolog-ically active in the morning. The physiologic stimulation by lunchmay be considered another indication of a normally functioningHPA axis. In other words, this group of men displayed signs of anexcellent functioning regulation of the HPA axis and of otherassociated neuroendocrine measurements as suggested by mea-surements of other hormones. These neuroendocrine functionsindicating health were thus found to be associated with a generallyhealthy condition in other variables. If this is the correct interpre-tation of the data, then relatively high cortisol concentrationswithin normal borderlines and with normal regulation is not nec-essarily associated with somatic abnormalities. Teleologically, thisinterpretation seems to make sense because normal endocrinefunctions are a sign of general health. These findings may helpexplain the different results in previous studies concerning therelation between cortisol secretion and somatic health. Not onlytotal cortisol secretion but also the kinetics of the HPA-axisregulation seem to be involved.

Table II also shows that, when stress-related cortisol secretionis considered in these men with a normally functioning HPA axis,as defined by a high variability of diurnal cortisol secretion, thereare positive associations to sagittal abdominal diameter, testoster-one, glucose, insulin, total and low-density lipoprotein cholesterol,and diastolic blood pressure. Thus, stress sensitivity of cortisolsecretion seems to be associated with somatic variables similar tothose seen in the metabolic syndrome, including visceral accumu-lation of an enlarged fraction of body fat, insulin resistance,dyslipidemia, and elevated blood pressure. In these men, totalcortisol was elevated in comparison with the control group, de-pending on the high cortisol values before lunch (Fig. 1). Withsuch sensitivity to stress demonstrated by elevated total cortisolsecretion, adverse symptoms of peripheral effects seem to be inproportion to these perturbations. It should be noted, however, thatmorning values were actually lower than in the control group,perhaps indicating a mildly perturbed physiologic regulation ofmorning cortisol levels by the HPA axis, which was much morepronounced in the men with low variability. This observationsuggests that not only total cortisol secretion but also the regula-tion of the kinetics of secretion are of importance for healthoutcomes.

Table II also shows the results in men with a pathologic,burned-out diurnal cortisol secretion. Basal cortisol secretionwas associated with mixed results including negative correlationswith the WHR, insulin, and triacylglycerols but positive correla-tions with blood pressure and heart rate. However, when lunch-and stress-related cortisol secretions are considered, strong, con-sistent positive correlations were found with all measurements,except testosterone, insulin-like growth factor-I, and high-densistylipoprotein cholesterol, where the correlations were negative.

These findings more clearly suggest that the measurements ofthe kinetics of HPA-axis regulation disclose abnormalities moreefficiently than total cortisol secretion, which was lower thannormal in this group. An elevated cortisol secretion may be in-volved in the pathogenesis of abnormalities in the men with anormally functioning HPA axis and high stress-related cortisolsecretion. However, elevated cortisol secretion is unlikely to beinvolved in the men with the burned-out cortisol secretion inwhom total cortisol secretion clearly was low. Apparently, low

morning values are particularly indicative of a disturbance ofHPA-axis regulation, and this circumstance, rather than cortisolitself, may be involved in the associations to somatic pathology.

Two other features seem to distinguish this group of men fromthe men with a supposedly normally functioning HPA axis. Thefirst is the consistently lower values of testosterone and insulin-likegrowth factor-I (Table II). In addition to the signs of HPA-axisperturbations, these low values are probably another indication ofneuroendocrine disturbances. Such disturbances are likely associ-ated with the abnormalities of HPA-axis regulation because ofinhibitory interactions between abnormal HPA-axis function andthe gonadal and growth-hormone axes.7 This is of interest for theassociations to somatic pathologies because low-testosterone orgrowth-hormone concentrations are able to induce both insulinresistance and visceral fat accumulation and associated metabolicabnormalities.35 Substitution with testosterone or growth hormoneto concentrations normal for the age is followed by impressiveimprovements, demonstrating the involvement of these hormonesin the association with somatic variables.35

Another feature seems to separate the burned-out group of menfrom the other men, namely the consistently elevated blood pres-sure and heart rate (Table II). These factors are likely signs ofactivation of the sympathetic nervous system. This is another signof perturbations in the central neuroendocrine or autonomic ner-vous system, in addition to the HPA, gonadal, and growth-hormone axes. The central regulation of the HPA axis and thesympathetic nervous system is tightly connected at several levels.7Stimulation of one of these centers is often followed by activationof the other. Furthermore, there is considerable evidence fromexperimental work that, when the activity of the HPA axis fails,the sympathetic nervous system takes over with elevated activity,perhaps as compensation.53 We suggest such a compensatorymechanism in the men with signs of poor HPA-axis function,expressing itself as a combination of low morning cortisol valuesassociated with elevated blood pressure and heart rate.

We have recently obtained additional evidence suggesting thatthe sympathetic nervous system is activated in parallel to abnormalHPA-axis activity. This idea was examined in a group of approx-imately 40 men with abdominal obesity, who on average had lowmorning cortisol levels, suggesting perturbed function of the HPAaxis. This was significantly associated with elevations in bloodpressure and heart rate, both before and during challenges by foodintake and laboratory stress tests, and with elevated excretion ofcatecholamine metabolites.54

Elevated activity of the sympathetic nervous system would beexpected to not only elevate blood pressure and heart rate but alsoincrease the mobilization of free fatty acids from adipose tissue.Elevated levels of free fatty acid is a robust finding in abdominalobesity55,56 and, although not measured in the studies discussed inthis review, would be an expected phenomenon in the group ofmen with a burned-out HPA axis because they were abdominallyobese. Free fatty acids exert profound peripheral effects on bothmuscles and liver to create insulin resistance.57,58

In summary, the results obtained after subdividing subjects intogroups with different HPA-axis function indicate a complex pic-ture whose components require analysis. The following featuresseem to emerge.

With a healthy HPA axis and little stress challenge, the normalphysiologic regulation of cortisol secretion is associated withphysical health. We speculate that this is a general indication ofnormally functioning neuroendocrinology in a broader sense thancortisol secretion alone would indicate. This was found in approx-imately two-thirds of the men.

With stress sensitivity, the HPA axis reacts by elevating corti-sol secretion, particularly during the period of the day whennormal regulatory functions are most active. We believe that in thiscase the elevated cortisol secretion may be involved in the devel-


opment of somatic pathologies; this seemed to be the case inapproximately one-fourth of the men.

In the condition of severe malfunction of HPA-axis regulation,manifesting itself as a functional burn out, diurnal cortisol secre-tion, with low total and, in particular, morning values, there areapparently additional signs of several neuroendocrine abnormali-ties. These abnormalities include inhibition of the gonadal andgrowth-hormone axes and an increased activity of the sympatheticnervous system, perhaps to compensate in maintaining allostaticfunctions. These latter abnormalities are known to be secondaryconsequences of HPA-axis perturbations. In concert, these neu-roendocrine abnormalities may affect peripheral tissues to createphysical abnormalities and disease, although direct cortisol effectsare unlikely to be involved. This was found in approximately 10%of the men.

It should be noted that cortisol elevation is apparently not theonly factor involved in the cascade of peripheral events after thesecombined neuroendocrine abnormalities. However, it seems likelythat elevated cortisol secretion as such has the most prevalentimpact in the pathogenesis of the abnormal health profile becauseit was found in approximately 25% of the men examined, whereasthe men with deranged HPA-axis function, in whom low cortisolsecretion was a less prevalent condition, constituted approximately10% of the men. The abnormalities, however, were more severeand robust in the latter group.

COMPARISONS WITH WORK IN EXPERIMENTALANIMALSMost of controlled stress research has been performed in experi-mental animals because similar studies are often difficult to per-form in humans. Comparisons with the results of controlled ex-periments suggest the mechanisms involved in human studies.

The observed abnormalities in the subgroups of HPA-axisfunction may be considered to consist of different stages, inanalogy with findings in prospective experimental work in ani-mals. In these animals studies, a normal stress reaction was foundto elevate cortisol secretion for a limited period. When frequentlystressed, the return to normal level was protracted, with elevateddiurnal cortisol secretion. A low, rigid burned-out cortisol secre-tion developed, with small diurnal variations.6 We speculate thatour population studies show a similar development. The conditionof stress sensitivity with elevated cortisol secretion seems to de-velop through frequent periods of stress into a burned-out cortisolsecretion, corresponding to the final stage in the animal experi-ments. Observations of frequent and prolonged exposure of thesemen to situations where environmental stress would be expectedare in line with such an interpretation. For example, long durationin poorly paid jobs could have an influence.59 In addition, severalmen with a burned-out HPA axis reported continued stress over theentire day of measurements. The data available thus far are onlycross-sectional, but we plan to refute or confirm this hypothesis byfollow-up studies.

Other lessons can be learned from the fully controlled animalexperiments and are pertinent to the human data referred in thepresent review. Dallman et al.60 examined the impact of standard-ized immobilization stress in rodents on the different diurnalactivity phases of the HPA axis. Rats have an inverse diurnalactivity curve in relation to humans, with a high activity during theearly night hours and low basal activity during the morning hours.The influence of stress seems to facilitate HPA-axis activity onlyduring the phases of high activity, i.e., in the early night hours.

Our observations in humans may be interpreted along theselines. In the men who were defined as being sensitive to stress, anelevated HPA-axis activity was found in the periods before lunchand during lunch, when the activity of the HPA axis is at its peakin humans (Fig. 1). This corresponds to the results of stress-induced facilitation of HPA-axis activity in rats, which also is seen

during the phase of high activity of the HPA axis. This in turnsuggests that the high prenoon cortisol levels in the stress-sensitivemen may be from frequent stress exposure for some period beforethe day of measurements, thereby sensitizing the HPA axis tocurrent stressors including food intake. The elevated cortisol re-sponses may therefore be considered an adaptive phenomenon. Inanalogy with the experimental data, these responses would beexpected to facilitate cortisol secretion regulated by factors inte-grated in the hypothalamic centers responsible for HPA-axisactivity.

Sensitivity to acute stressors is particularly elevated in rodentsduring the low-activity phase of the HPA axis.60 In humans, thelow-activity phase occurs in the evening and early night hours.Specific measurements, e.g., nocturnal registrations, of this sensi-tivity were not performed. However, sleep disturbances are fre-quent with perturbations of HPA-axis regulation,61 which mayindicate nocturnal stress.62 Clearly, nocturnal measurements ofcortisol secretion would be informative in this situation.

The Feedback Control

The function of the feedback system is usually tested by admin-istration of the synthetic glucocorticoid dexamethasone. For ex-ample, when diagnosing Cushings syndrome, 1 mg of dexameth-asone is routinely given and cortisol is measured the morningbefore and after administration. Cortisol secretion at those pointshas normally decreased below a clinically defined level.

Using lower doses of dexamethasone in milder forms of feed-back regulatory errors than in Cushings syndrome and depressionhas been tried and found to be informative.50 For example, subjectsin certain professions under prolonged pressure have been found tosuppress cortisol secretion inadequately when doses of dexameth-asone lower than 1 mg have been used.50

A problem with evaluation of the results of suppression withlow doses of dexamethasone is that there are no established thresh-old values below which the cortisol values are considered normallysuppressed. One method of evaluation that has been used is cal-culating the absolute decrease of cortisol values with dexametha-sone administration. This is, however a complex measurement thatdepends on the level of both the noninhibited morning value andthe suppressed concentration. An additional difficulty is that morn-ing cortisol levels are secreted in large peaks, making determina-tions of noninhibited morning cortisol levels difficult. To diminishthis problem, determination of several morning cortisol levels isuseful. An additional problem is that basal morning cortisolsvalues may be influenced by the laboratory milieu where the test isperformed and the intravenous puncture to obtain serum formeasurements.

Dexamethasone inhibition with conventional doses has beenfound to be normal in obesity. By using doseresponse measure-ments, we found that, whereas the conventional dose of 1 mgshowed a complete inhibition,38 cortisol suppression seemed to bediminished at low levels of dexamethasone in men with abdominalobesity.51 This study was based on four noninhibited morningcortisol levels, and the results were expressed as the absolutedecrease of morning cortisol levels measured in serum. The resultsindicated a decreased sensitivity of the inhibiting system, whereasresponsiveness, presumably measured with higher dexamethasonedoses, appeared to be unaffected.

In the population studies, a dose of 0.25 or 0.5 mg was used,with saliva cortisol collected at home and suppression measured asthe absolute decrease of the average of two basal morning valuesof cortisol. We are aware that the results are a mixture of theinfluence of the morning values and the inhibited values. This isprobably significant because low morning cortisol values, found insome of the conditions described in the preceding sections, wouldby themselves indicate an abnormal function of the HPA axis.Using only suppressed values has not been considered possible


because of the lack of borderlines that would be considered nor-mal. A deficient control of cortisol secretion after HPA-axis chal-lenges by food intake and by perceived stress was often found inparallel with a decreased dexamethasone suppression, suggestingthat the dexamethasone test employed was informative. Further-more, results of tests of the function of the peripheral GR inadipose tissue in fully controlled tissue-culture experiments seemto parallel the dexamethasone inhibition of cortisol in doseresponse experiments.63

With these caveats, we have interpreted the suppression with0.5 mg of dexamethasone to indicate that the feedback mechanismis mildly insufficient in parallel with indications of perturbations ofHPA-axis regulation.42 To what extent this is from low morningvalues or remaining elevated suppressed levels of cortisol cannotcurrently be decided. The results of poor control of cortisol afterstress and food intake suggest that the feedback mechanism maynot be fully efficient when there are signs of perturbations of theregulation of the HPA axis.

A supposed mild blunting of the feedback mechanism may besecondary to a downregulated GR density by elevated cortisolsecretion.6 With continued pronounced elevation of cortisol con-centrations, as in Cushings syndrome or depression, cognitivefunctions become damaged; at later stages, atrophies are occurringof efferent dendrites from the GR positions in the brain, eventuallyresulting in lacunae with loss of brain substance.6 Because blunteddexamethasone suppression appears mainly with low total cortisolsecretion,42 secondary downregulation of GR density by elevatedcortisol appears to be unlikely, and a primary weakness of theregulatory system should be considered.

In summary, the abnormally elevated level of cortisol secretionduring the high-activity phase of the HPA axis in about one-thirdof the men studied may be due to an increased central facilitationof HPA-axis activity, a blunted feedback control, or both.

Two types of GR are present in the regulatory brain centers, GRI and GR II. GR I is equivalent to the mineralocorticoid receptorand has a higher affinity for cortisol (Kd ; 0.5 nmol) than does GRII (Kd ; 2.5 nmol).64 Therefore, it is presumed that the GR IIregulates elevated cortisol secretion during phases of high HPA-axis activity and during challenges of the axis by stress and foodintake. Similarly, with the higher affinity, the GR I takes over theregulatory function of the HPA axis during low activity.

The abnormally elevated prenoon and lunch values of cortisolin the men with high sensitivity of stress-related cortisol may becaused by either a central facilitation of the HPA axis or a dimin-ished feedback control by GR II. The findings of blunted dexa-methasone suppression and the association with polymorphisms ofthe GR gene locus (discussed later) suggest involvement of thefeedback system.

There is considerable evidence that chronic stress in bothhumans and animals is followed by diminished feedback control.This has been reported after the stressful conditions of markedweight loss,6567 anorexia nervosa,68,69 diabetes mellitus,70,71 anddepression.7274 Rats with diabetes75 or exposed to cold76 show adecreased sensitivity to the suppressive effects of exogenous ste-roids on the HPA axis.

Studies of GR number in cytosolic preparations from specificbrain localizations have been performed. Hypothalamic and pitu-itary binding is usually normal. However, preparations from thehippocampal area showed a decreased binding in chronicallystressed rats in several,7779 but not all,80 studies.

MOLECULAR GENETIC STUDIES

The HPA Axis

Detailed information concerning the phylogenetic expression ofthe syndrome studied has allowed us to investigate potential ge-netic factors by using the candidate gene approach with the tech-

nique of restriction fragment-length polymorphism. A first targetwas the GR gene locus. As reported previously,8183 we found thatthe polymorphism, localized to the first intron of the GR gene,discoverable with the restriction enzyme Bcl I, is associated withabdominal obesity, insulin resistance, and elevated blood pressure.In addition, and of direct interest for the HPA-axis regulation, thispolymorphism was associated with an approximately 40% increasein cortisol secretion after lunch in homozygote men in comparisonwith men with the presumed wild-type allele. Such elevated cor-tisol secretion is a major finding in the stress-sensitive men whosecrete elevated levels of cortisol after lunch, suggesting a func-tional association with the regulation of HPA-axis activity. Theprevalence of homozygotes was 14% in the population sample ofmen. Heterozygote men showed similar perturbations, althoughless pronounced.84

That this polymorphism is localized to an intron does notexclude a functional importance in the regulation of transcription,particularly because it is localized in the intron preceding the firstcoding exon. However, there was no overrepresentation of thispolymorphism among the men with perturbations of HPA-axisactivity (unpublished observations), suggesting that this polymor-phism has no functional importance or that a decreased GR func-tion can be induced secondary to the facilitation of central HPA-axis activity. Alternately, this polymorphism may indicatefunctional polymorphisms in the vicinity of the gene.

Mutations of the gene resulting in a defective GR protein areunlikely to occur because they would be followed by severedisease.85 However, defects resulting in regulatory errors of GRdensity, e.g., by interfering with the rate of transcription of thegene, seems to be a potential possibility, which would also fit wellwith the phylogenetic expression of the pathologic findings, inparticular the indications of a defect-feedback regulation.51

There have been recent reports of trinucleotide repeats (CAG)that, when abnormal in number, may interfere with the transcrip-tion rate of steroid hormone-receptor genes, particularly when suchrepeats are localized to early exons.86 Therefore, exon 2 of the GRgene, which is the first coding exon, was sequenced and CAGrepeats analyzed. In comparisons between men with suspectedgenetic abnormalities as judged from the measurements of HPA-axis activity and men without such abnormalities and a group oflaboratory personnel, no abnormalities were found.63

The restriction enzyme Tth 111-I detects a polymorphism in the59 flanking region of the GR gene locus. Such a polymorphism wasassociated with basal cortisol secretion in the men studied. Theprevalence of homozygotes is about 9%.87 Potential associationswith other factors are difficult to judge because of small numbersand may not be expected because basal cortisol secretion is notstrongly associated with somatic pathologies.

In summary, several phylogenetic characteristics indicatechanges in the perturbation of HPA-axis control that may beexplained, at least in part, by a functional defect of the controllingfunction of central GRs, i.e., a perturbed regulation of GRdensity. The findings of polymorphisms associated with suchfunctions are compatible with, but merely indicative of, effectson the regulation of GR density. The promoter region of the GRgene may be involved, and the first part of this domain is beingsequenced.

The Sympathetic Nervous System

The sympathetic nervous system is most likely involved in theneuroendocrine perturbations studied, particularly in putative latestages of a development of abnormalities. Polymorphisms of thissystem therefore become of interest and have also been studiedwith restriction fragment-length polymorphism.

The dopaminergic system is involved in blood-pressure regu-lation through dopamine receptor I, which regulates salt retention,and dopamine receptor II, which controls catecholamine outflux


from synapses.88 A polymorphism of dopamine receptor II, dis-closed by the restriction enzyme Nco I, was associated withconsiderably elevated blood pressure in the men studied.89 Al-though only a statistical association, the possibility of a suscepti-bility to diminished inhibition of norepinephrine secretion in nerveendings is of interest because of its potential regulation of netactivity in the sympathetic nervous system. This activity may haveconsequences for both metabolic perturbations by increased mo-bilization of free fatty acids and the pathogenesis of early, hyperki-netic stages of primary hypertension, which is considered to beinduced by central activation of the sympathetic nervous system.This finding may attract research in this direction.

Leptin is involved in the regulation of satiety, but recent re-search in rats has convincingly shown that leptin also signals to thecentral sympathetic nervous system through the leptin receptor inthe hypothalamic region.90 When the leptin receptor shows muta-tions, these signals are prevented. Hypertension is present in mostanimal models of obesity with raised leptin levels. However, themutated leptin receptor seems to protect the animal from hyper-tension, despite the presence of massive obesity and large eleva-tions of both insulin and leptin.90

The restriction enzymes Hae III, Msp I, and BstU I revealpolymorphisms in the leptin-receptor gene locus (Lys109Arg inexon 4, Gln223Arg in exon 6, and Lys656Asn in exon 14, respec-tively). Men who are Arg109 homozygotes (9%) and Arg223homozygotes (26.8%) have considerably lower blood pressure,independent of other variables. Men with obesity and elevatedleptin levels and with the normal Lys109Lys allele had 12.4 and6.9 mm Hg higher systolic and diastolic blood pressures, repec-tively, than did men homozygous for the Arg allele. Hypertensivemen had higher BMI and leptin levels but were essentially free ofthe leptin-receptor polymorphism. These results suggest that onlymen with the normal alleles of the leptin receptor have an elevatedblood pressure and that polymorphisms of the receptor, whenpresent, seem to protect these men from hypertension, even thosewho are obese and have elevated leptin and insulin levels.91 Thesefindings suggest that hypertension in obesity is to some extentdependent on the leptin system and that perturbed or absent signalsfrom the leptin receptor may protect against hypertension in obe-sity. This in turn may explain the observation that not all obesemen are hypertensive.

These are statistical-association studies that may initiate furtherresearch into this direction. The findings are of interest becausethey indicate another neuroendocrine pathway involved in thecomplex abnormalities of the central regulatory system associatedwith HPA-axis perturbations. Interestingly, the polymorphisms ofthe leptin receptor were associated with lower-than-average valuesof BMI and not with obesity, which would have been expected ifthese polymorphisms were associated with perturbations of satietysignals. The reason for such an apparent diversion of signals fromthe leptin receptor is not known.

The leptin system, however, seems to be associated with theHPA-axis perturbations reviewed above. Such abnormalities arefollowed by an elevated BMI and leptin in statistical-path analyseswith a close goodness of fit.92 Results of preliminary studies havesuggested that administration of glucocorticoids over a week to agroup of moderately, peripherally obese women is followed byincreased leptin levels and energy intake (Udden et al., unpub-lished observations), suggesting that glucocorticoids may induceleptin resistance and, in the long run, obesity. Such an increase hasbeen shown in rats in elegant experiments, where adrenalectomy isfollowed by pronounced leptin sensitivity, which is reversed in adose-dependent manner when glucocorticoids are substituted, re-sulting at higher doses in leptin resistance, hyperphagia, andobesity.93

These studies suggest an interaction between the HPA axis andthe leptin system and may explain the reason why centralizationof body fat, as measured with the WHR, and enlarged body fatmass, as indicated by the BMI, are often closely statistically

associated35 and apparently dependent on perturbations ofHPA-axis activity.

CORTISOL METABOLISM

Cortisol secreted from the adrenals is exposed to enzymic trans-formations in peripheral target cells. The enzymes involved are the11-b-hydroxysteroid dehydrogenases (11b-HSD), which transfercortisol to the less active cortisone (enzyme 2) or cortisone tocortisol (enzyme 1).94 11b-HSD2 was originally thought to protectcertain tissues from excess cortisol exposure from the mineralo-corticoid receptor, particularly in the kidney,95 but has subse-quently been found in a number of other tissues, including adiposetissue, muscle, and liver,96 suggesting a more generalized functionof importance for the net exposure of these tissues to cortisol.Furthermore, if the inactivation of cortisol systemically is suffi-ciently large, the feedback function regulating cortisol secretion bythe HPA axis would be expected to allow elevated cortisol secre-tion. This in turn would be seen as an increased turnover ofcortisol, which has been reported in obesity. Thus, there is arealistic possibility that the increased secretion of cortisol in hu-man obesity would indeed be a consequence of an elevated pe-ripheral inactivation of cortisol. Because adipose tissue containsthe enzyme, such elevated cortisol turnover could be consideredsecondary to the elevated body fat mass in obesity.97

There are also important enzymic transformations in the A ringof the cortisol molecule including 5-a and 5-b reductases. Theactivity of these enzymes is essentially not reversible and leads toremoval of active glucocorticoids, with the b-isoform throughbile-acid metabolism.98

The net impact of cortisol on peripheral GRs is consequentlydependent not only on cortisol secretion but also on the fate ofcortisol in the periphery. The effects of glucocorticoids are exertedby the GRhormone complex, which interacts with appropriategenes to induce protein synthesis. The magnitude of this impactdepends not only on the density of the available GRs in thecytoplasm but also on the concentration of active cortisol. This inturn is dependent on the transformation of cortisol to cortisone orof cortisone to cortisol locally, depending on the 11b-HSDspresent. This transformation may then lead not only to localmodifications of net cortisol effects but also to variations in sys-temic glucocorticoid concentrations in the circulation. Thus, it isclear that these pathways have a potential to modify peripheralcortisol impacts. The question then is, How quantitatively impor-tant are these peripheral mechanisms for local and systemic cor-tisol effects?

First, infusion of cortisone in humans, where endogenous cor-tisol production has been inhibited by preceding suppression bydexamethasone, is followed by a limited elevation of plasmacortisone but a clear increase in cortisol, demonstrating the con-siderable activity of the 11b-HSD1 in humans.99 This activity hasactually provided the basis for cortisone therapy in the clinicalsetting. Carbenoxolone, an inhibitor of 11b-HSD activity, im-proves glucose metabolism, an expected outcome of lower cortisollevels.100

In adipose-tissue stromal cells, 11b-HSD1 activity has beenfound and is apparently higher in omental than in subcutaneousfat.101 As a possible consequence, resulting local cortisol produc-tion would increase visceral fat mass and possibly, by spillovereffects, diminish muscular insulin sensitivity and thus contribute tothe insulin resistance of visceral obesity. Although intriguing, thisexplanation seems unlikely for at least two reasons. First, the massof visceral adipose tissue is comparably small, amounting to some10% of total adipose-tissue mass, even in visceral obesity52; there-fore, the capacity of this mechanism would have to be considerableto exert systemic effects. Second, tissue culture of human preadi-pocytes is difficult to perform in a way to allow quantitative


comparisons because of the risk of overgrowth of cells other thanadipocyte-precursor cells.

There have been reports showing an increased secretion of5-a-reductase metabolites in obese humans that is more pro-nounced in abdominal obesity.102,103 If this is a primary defect, itwould be expected to lower circulating cortisol concentrations andbe followed by elevated cortisol secretion through diminishedfeedback control. This would be further pronounced by a de-creased activity of the 11b-HSD1 activity in the liver.

It seems clear that the metabolic fate of cortisol in the peripheryhas a potential to alter not only local effects in target tissues butalso the overall secretory regulation of cortisol. The overall pictureis complex and needs further exploration and methodologic devel-opments to allow better clarification. The picture becomes evenmore complex by the fact that the key enzymes involved areinfluenced by several other factors in the ongoing endocrine andmetabolic events. For example, glucocorticoids, cytokines, insulin,growth hormone, and stress are all involved in the regulation ofthese enzymes. In addition, differences in receptor sensitivityacross patient groups and across tissues have been reported, addingto the complexity of this field.97

IS THE INCREASED CORTISOL SECRETION INOBESITY FROM CENTRAL OR FROM PERIPHERALFACTORS?

The question then remains as to how critical cortisol is in humanobesity. There seems to be two prevailing theories, one suggestingthat the perturbations of cortisol secretion is of central origin andanother where peripheral cortisol metabolism is the primary factor.There is clearly evidence for both, and an attempt will be made toweigh the arguments for one against the other and examine thepotential likelihood of their involvement as primary or secondaryevents in obesity.

The first question is whether or not obesity is a consequence ofderanged cortisol secretion or metabolism or whether these de-rangements are consequences of the obese state. Both the centraland peripheral hypotheses agree on the fact that cortisol secretionis increased in human obesity. The peripheral hypothesis states thatobesity is the primary factor modifying peripheral cortisol metab-olism, so that cortisol turnover is elevated because of a secondary,compensatory secretion of active cortisol by central mechanisms.The central hypothesis states that increased cortisol secretion hasits origin in an increased stimulation of central regulatory mech-anisms, including deficient feedback, that may be secondary to theincreased cortisol secretion and may be amplified by geneticdefects.

The hypothesis that the increased or deranged cortisol secretionin abdominal obesity has a central origin is supported by a numberof observations indicating statistical associations with factorsknown to be followed by elevated cortisol secretion. These factorsinclude psychosocial and socioeconomic handicaps, depressiveand anxiety traits, smoking, and increased alcohol consump-tion.104,105 One may argue that these statistical associations do notprove causality, but it is difficult to imagine that a cause-and-effectpathway would not start out from such factors, which are wellknown to be followed by elevated cortisol secretion. In addition,there is a graded impact that is apparently time dependent,59 whichcould serve as a surrogate measurement for an intervention trial.Controlled intervention studies have been performed in primatesother than humans where moderate psychosocial stress is followednot only by enlarged adrenals but also by a diminished efficiencyof the feedback control.106 Smoking and alcohol consumption areprevalent in abdominal obesity104,105 and are followed by elevatedactivity of the HPA axis,107,108 and both cessation of smoking anddiminished alcohol intake are followed by normalization of corti-sol secretion.107,108 This is also a well known consequence of the

treatment of depression.109 It seems difficult to understand theseobservations in terms of a primary increase in peripheral cortisolmetabolism.

Nevertheless, the observations of an increased peripheral cor-tisol metabolism in abdominal obesity are quite convincing, but itis difficult to understand how abdominal obesity would be acondition with cortisol-induced pathologies if a large fraction ofcortisol is inactivated before inducing peripheral effects. Onecould speculate and suggest that peripheral inactivation of cortisolin obesity may serve as a protective mechanism for excess expo-sure of the organism to cortisol. Parallel studies of the centralsecretion and peripheral metabolism of cortisol are needed toresolve this problem.

Perinatal Factors

Based on a considerable body of evidence, perinatal factors havebeen implicated in the pathogenesis of central obesity and itscomplications through elevated cortisol secretion.110 Childrensmall for their gestational age often seem to develop centralobesity and the metabolic syndrome in adulthood. Results of recentstudies have suggested the mechanisms involved. Adult subjects,born small for their gestational age, have elevated morning cortisollevels and abnormally sensitive responses to low doses of adreno-corticotropin challenge, suggesting involvement of the HPAaxis.111

There is considerable literature available in which the influenceof various perinatal factors on the regulatory function of the HPAaxis has been studied in experimental animals. This has recentlybeen the subject of an excellent review,112 which is briefly sum-marized here. First, there is evidence that intrauterine exposure toglucocorticoids is followed by offspring small for their gestationalage in both humans and animals. Perinatal exposure to stress andglucocorticoids has repeatedly been found to influence the HPAaxis in adult life due, at least partly due to changes in central GRs,thus regulating the feedback of the HPA axis.

Normally there is a barrier between the maternal and fetalcirculations that protects the fetus from the much higher cortisollevels of the mother. This protection is probably exerted by therapid inactivation of maternal cortisol by 11b-HSD2 in the pla-centa. Apparently, the efficiency of this enzyme differs consider-ably, giving room for variations in fetal exposure to maternalcortisol. The activity may also be affected by external factors, andsome exogenous glucocorticoids are not metabolized by the en-zyme. In addition, placental corticotropin-releasing hormone maybe stimulated by both maternal and fetal stress. The exposure tostress in the early neonatal period is also followed by remainingdysregulatory errors of the HPA axis in adult life. The impact ofsuch factors is apparently subtle and variable.

Thus, there are a number of factors during the perinatal periodthat are able to permanently determine the regulation of HPA-axisactivity in adult life. These factors include not only glucocorticoidsbut also stressors that may act through increased glucocorticoidexposure of the fetus. Cytokines are powerful activators of theHPA axis and may be active during maternal infections. Theeffects of such agents differ depending on time of exposure, sex,and type of cytokine. The resulting programming seems to affectdifferent systems, not only the HPA axis but also body composi-tion, sex steroid hormones, and insulin sensitivity.113

For obvious reasons, most of these experiments have beenperformed in experimental animals, mainly rodents. Availableevidence in humans and primates suggests that the animal data arelargely applicable to humans. The sensitivity of the systems ex-posed to various impacts during the perinatal period, including theregulation of the HPA axis, highlights the importance of thisperiod for the programming of systems that, when affected, may befollowed by disease in adult life.

This small-baby syndrome shows remarkable similarities to


the observations noted in studies in the adult population. Theelevated morning cortisol levels reported in studies of adults bornas small for their gestational age111 are an apparent differencebecause the morning cortisol levels that we have observed tend tobe low. The elevated morning cortisol levels seen in adults with thesmall-baby syndrome may result from their presumed stress sen-sitivity, which would be expected to be followed by elevatedcortisol levels during the sampling procedure for cortisol measure-ments. Because of the high variation of morning cortisol values, itwould be interesting to observe how the diurnal regulation ofcortisol secretion functions and observe the results of challenges tothe HPA axis. We do not as yet have data on birth weight andtherefore cannot directly compare, e.g., the prevalence of thepresumed pathways through genetic susceptibility, perinatal pro-gramming, and environmental challenges. The development of thesyndrome may occur by contributions from all these pathways.

Involvement of Central Transmitters and NeuropeptidesThe overview has indicated an involvement of several neuroendo-crine systems, including the HPA axis, hypothalamic, gonadal, andgrowth-hormone axes, the central sympathetic nervous system,and the leptin system. These are all closely interconnected at acentral level and depend on several controlling systems in acomplex interplay.7

HPA-axis perturbations are followed by inhibitions of gonadaland growth-hormone secretion at several levels.7 These inhibitionsare probably followed by peripheral consequences.

The interconnections between the HPA axis and the sympa-thetic nervous system are of particular interest because both trans-fer signals to the periphery of central interactions. Adrenoceptordensity in the hypothalamic region seems to be sensitive to glu-cocorticoid exposure, in particular the a-2 receptor, the density ofwhich changes in accordance with diurnal corticosterone levels,114decreases with adrenalectomy, and is restored by glucocorticoidreplacement.115

Conversely, catecholamines stimulate the HPA axis. Cat-echolamines exert facilitating effects on the HPA axis, resulting insecretion of corticotropin-releasing hormone, adrenocorticotropin,and cortisol. This action has been shown after administration ofexogenous catecholamines or a-1 adrenoceptor agonists and ofelectric or chemical stimulation of catecholaminergic pathways.Furthermore, increased central catecholamine turnover after phys-iologic or pharmacologic stimuli is followed by elevated HPA-axisactivity. Results of recent experiments have suggested that glu-cocorticoids also modulate adrenoceptor number and expression,thereby facilitating the central effects of catecholamines. A block-ade of such events is followed by inhibited HPA-axis activity. Theinhibitory effect seems to be mediated by the a-adrenergic 2receptor subtype.53

Thus, there is a mutual interdependence between the HPA axisand the central sympathetic nervous system. This interdependencemay have consequences for obesity and obesity-related abnormal-ities through peripheral pathways.

The HPA axis and the serotoninergic system also interact atseveral levels (for review, see Chrousos and Gold7). The multipleeffects of serotonin include the involvement of factors associatedwith HPA-axis activity such as depression, anxiety, alcoholism,and a craving for carbohydrates, all of which seem to be associatedwith a relative deficiency of serotoninergic activity.116 All thesefactors have been shown to be associated with central obesity.35Hyposerotonergic obesity has been described,117 and drugs thatincrease synaptic concentrations of serotonin have been used suc-cessfully to treat obesity.7

We have recently completed a study with the aim of increasingsynaptic concentrations of serotonin in a group of men withabdominal obesity, abnormal HPA-axis activity, increased activityof the sympathetic nervous system, and associated peripheral met-abolic abnormalities. The results of this pilot study were an ap-

parent improvement in the abnormalities of the HPA axis andsympathetic nervous system and the tendencies to diminish met-abolic perturbations.118 This result should be repeated in a largerstudy.

Among the multitude of effects of the dopaminergic system,there is also involvement in the regulation of the sympatheticnervous system from several directions (for review, see Chrou-sos119). This would be expected to exert an impact on bloodpressure and metabolic regulation. The association studies withrestriction fragment-length polymorphism analyses of dopamine-receptor 2 and blood pressure have been mentioned. Another studyhas shown associations between the polymorphisms of this recep-tor and subjects with a parenteral history of obesity, adult onset ofobesity, and carbohydrate preferences in food intake.120 Subordi-nate female Cynomolgus monkeys develop visceral obesity, andpharmacologic studies have indicated that the dopamine-receptor 2function in those monkey was defective.106

Clearly the leptin system is also involved in these complexinteractions between the central and neuroendocrine systems. Al-though a few case reports have been published concerning mal-function of the leptin system on a genetic basis, such abnormalitiesseem to have little relevance for common human obesity. Thephenomenon of leptin resistance has not been explained and mayhave important information concerning regulatory errors in humanobesity. Interactions with the sympathetic nervous system seem tohave been established.

Based on these studies, perturbations of HPA-axis regulationseem to be associated with several other central systems, includingthe adrenergic, serotoninergic, dopaminergic, and leptinergic, andother central interactions (for review, see Chrousos and Gold7 andChrousos119). Some progress has occurred in studies in humans inthis field, which should be a rewarding area for further studies.

GENERAL SUMMARY

Cortisol secretion in obesity has attracted considerable attention,and a great number of publications are available. The interest hasprobably derived from the fact that most animal models of obesitydisplay an increased cortisol secretion and are cured by adrenal-ectomy. Furthermore, clinicians are aware that certain obese pa-tients have a Cushingoid appearance.

Previous studies in general have shown an increased cortisolsecretion and an elevated peripheral fractional turnover rate, re-sulting in normal or even lower-than-normal level of cortisolsecretion. Unfortunately, most of these studies have not focused onthe subgroups of central, abdominal, and visceral obesity, wherecortisol secretion would be expected to be elevated because of thehypercortisolemic appearance of this condition, which is alsoassociated with high risks for disease development.

In mild or moderate conditions of elevated cortisol secretion,conventional clinical methods for diagnosis are probably not suf-ficiently sensitive. Recent work has used saliva cortisol measure-ments in abbreviated diurnal measurements in the basal and stim-ulated conditions (standardized food intake and perceived stress).When applied on a population basis, such examinations may showpathologic phenomena associated with obesity and its complicat-ing pathologic features.

In Swedish middle-aged men (women are currently being ex-amined), such measurements have produced the expected widespread of data. By using a statistical weighting procedure, twotypes of diurnal curves have been discerned, one normal and onepathologic, with low cortisol secretion and little variation in aminor fraction (about 10%). Men with the normal day curve wereassigned to groups with high (about 30%) and low stress-relatedcortisol secretion. Men with high stress-related cortisol secretionhad higher cortisol values over the day, particularly before andduring lunch, than did the men with low stress-related cortisolsecretion. These men also had visceral obesity and a cluster of


metabolic risk factors, as in the metabolic syndrome. These patho-logic features could well have been induced by the elevatedcortisol secretion.

The men with pathologically burned-out cortisol secretion hadlower cortisol values, particularly in the morning. These menshowed robust positive associations with abdominal obesity, met-abolic variables, blood pressure, and heart rate, and low secretionsof testosterone and growth hormone. In this subgroup, abdominalobesity and its associated metabolic abnormalities are unlikely tobe caused by the cortisol secretion but may be from the decreasedsecretion of the other hormones and to an elevated activity of thesympathetic nervous system.

The feedback control of the HPA axis, as examined with thelow-dose dexamethasone inhibition test, is probably mildly per-turbed in men with abdominal obesity.

It should be reemphasized that the studies referred to wereperformed in men. In current analyses of similar studies in women,several differences have been found. For example, hyperandroge-nicity, probably of adrenal origin, at least in part, seems to exert amore powerful impact than cortisol on the risk-factor pattern,including abdominal obesity (unpublished observations).

This analysis shows the complex associations between obesityand the function of the HPA axis and cortisol secretion. Elevatedcortisol secretion was found to be associated with abdominalobesity only in men with a normal basic HPA-axis function and anincreased sensitivity to stress; in a smaller group of men withabdominal obesity, cortisol secretion was low. These distinctionsmay explain the different results in previous reports in theliterature.

These results are in agreement with data obtained in fullycontrolled animal experiments insofar as chronically stressed ratsdisplay a facilitated HPA-axis activity during the active phases ofHPA-axis activity, similar to the men with high stress sensitivity.Furthermore, when such stress exposure is prolonged, sex-steroidand growth-hormone axes are inhibited, the HPA axis becomesburned out with low activity, and a compensatory increase of thesympathetic nervous system is initiated. This result may corre-spond to the men with low activity in the HPA, gonadal, andgrowth-hormone axes, with signs of elevated sympathetic nervoussystem activity. In humans, this low activity could be interpretedas a staging from normal HPA-axis function through frequent orchronic stress periods to a final stage with severe neuroendocrine,endocrine, metabolic, and hemodynamic perturbations. Results ofthese studies in men show strong statistical associations to stress-related psychosocial and socioeconomic handicaps, psychiatrictraits, alcohol intake, and smoking, all of which are activators ofthe HPA axis, and probably provide background factors for re-peated or chronic challenges.

Elevated cortisol secretion is probably involved in abdominalobesity with its complicating pathologies. It seems reasonable toassume that this kind of obesity is from central facilitation of theHPA axis in combination with a perturbed feedback control. Theinfluence of the peripheral metabolism to inactivate cortisol andthen induce elevated cortisol secretion has been suggested. Thisnotion seems less likely than the pathogenetic pathway of a centralfacilitation of HPA-axis activity because of the data supportingsuch an explanation, although much of the data is circumstantial.Data suggest that the pathogenesis of the syndrome also may beinfluenced on by perinatal factors that determine the sensitivity ofthe HPA axis.

Genetic factors are most likely involved, and preliminary find-ings in association studies have indicated the involvement of theGR gene locus, as well as concerning the sympathetic nervoussystem, dopamine-receptor 2, and the leptin receptor.

In short, there are a number of observations indicating aninvolvement in obesity, in particular abdominal obesity, of severalcentral regulatory systems, including the HPA, gonadal, growth-hormone, and leptin axes, the sympathetic nervous system, and thecentral adrenergic, serotoninergic, and dopaminergic systems. All

these systems are tightly interconnected at several levels. It seemslikely that abdominal obesity and its associated complications arederived from combined abnormalities in the regulation of thesesystems, where the HPA axis and cortisol secretion play a centralrole but are probably not the only factors of importance.

The associations between cortisol and obesity appear to bemuch more complicated than anticipated. Cortisol is clearly not theonly peripheral trigger of adverse effects, which may explain theconfusion in this area. It seems likely that the pattern in whichcortisol is secreted is equally important as the total secretion ofcortisol. Therefore, it seems necessary for future studies to exam-ine the kinetics of cortisol secretion and the response to standard-ized challenges when examining the role of cortisol, not only inobesity and its complications but also in human disease from abroader aspect.

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