International Textbook of Obesity - part 5 pptx

Figure 15.1 Behavioral characteristics of socially dominant (Dom; white bars) and subordinate (Sub; black bars) female monkeys. Subordinates receive more aggression, are groomed less—that is they spend less time in positive affiliative behavior, spend more time alone, and they spend more time vigilantly scanning their social group than dominants. Freq./h : fre- quency per hour; % time : percentage of time spent. (Based on data from Shively et al. (13,14)) PSYCHOSOCIAL FACTORS THAT INFLUENCE CORONARY ARTERY ATHEROSCLEROSIS AND CHD RISK IN FEMALE MONKEYS Social Status Cynomolgus monkeys typically live in large social groups that are characterized by complex social relationships. Complex social living includes the possibility of social stress effects on health. A major social organizing mechanism of monkey society is the social status hierarchy (12). Female monkeys with low social status, or subordinates, are behav- iorally and physiologically different from domi- nants. The distinguishing behavioral characteristics of subordinates are depicted in Figure 15.1. Subordi- nate females are the recipients of about three times the hostility or aggression of their dominant counterparts. They are groomed less, i.e. they spend less time in positive affiliative behavior. They spend more time vigilantly scanning their social group than dominants. The purpose of the vigilant scann- ing appears to be to track and avoid dominants in order to avoid aggressive interactions. Subordi- nates also spend significantly more time alone than dominant females (13—15). Primates typically com- municate non-verbally by touch, facial expressions and body language or postures. Although human primates also are able to communicate with lan- guage, they still rely heavily on non-verbal com- munication. When a female monkey spends time alone, it means that the monkey is not in physical contact or within touching distance of another monkey. Rather, the monkey is socially isolated. This is intriguing given the observations in human beings that suggest that social support is associated with reduced CHD risk, and observations in mon- keys suggesting that social isolation increased cor- onary artery atherosclerosis and heart rate (16—18). Thus, it seems that subordinates are subject to hos- tility and have very little social support. Physiological characteristics of subordinates that distinguish them from dominants include differen- ces in measurements of adrenal function. Following dexamethasone suppression, the adrenal glands of subordinate females hypersecrete cortisol in re- sponse to an adrenocorticotropic hormone chal- lenge, and are also relatively insensitive to cortisol negative feedback (15). Since the hypersecretion of cortisol is typically viewed as indicative of a stressed individual, these findings imply that, in general, subordinate females are stressed females. Subordinate females also have a greater number of abnormal menstrual cycles than dominant fe- males (8). Progesterone concentrations are lower during the luteal phase, and estradiol concentra- tions are lower in the follicular phase of the men- strual cycles of subordinate females. Moderately low luteal phase progesterone concentrations indi- cate that although ovulation may have occurred, the luteal phase was hormonally deficient. Very low luteal phase progesterone concentrations indicate an anovulatory cycle (19,20). Thus, stressed, subor- dinate females have poor ovarian function com- pared to dominants. Subordinate females with poor ovarian function have more coronary artery atherosclerosis than their dominant counterparts (Figure 15.2). Indeed, the coronary artery atheros- clerosis extent in these subordinate, stressed females is comparable to that found in both ovariectomized females and males (5,8). The effects of stress on ovarian function in women are difficult to evaluate because of the diffi- culties in characterizing menstrual cycle quality over long periods of time. However, the results of several studies are consistent with the hypothesis that stress can have a deleterious effect on ovarian function in women (21—23). Furthermore, mechan- 204 INTERNATIONAL TEXTBOOK OF OBESITY Figure 15.2 Coronary artery atherosclerosis (measured as plaque extent) in males and in females in different reproductive conditions. Among females: gray bars : ovariectomized females; black bars: intact socially subordinate females with poor ovar- ian function; white bars : intact socially dominant females with good ovarian function. (Based on data from Hamm et al. (5), Adams et al. (8)) istic pathways relating stress to impaired reproduc- tive function in female primates have been identifi- ed, suggesting that the stress—ovarian function im- pairment hypothesis is plausible from a physio- logical perspective. Activation of the hypothalamic- pituitary-adrenal axis, endogenous opioid path- ways, increased prolactin release, and changes in sensitivity to gonadal steroid hormone feedback have all been proposed to mediate the effects of behavioral stress on the reproductive system (24—30). Intriguingly, women with hypothalamic amenorrhea also have increased hypothalamic-pi- tuitary-adrenal activity similar to that observed in subordinate female cynomolgus monkeys (31). The relationship between poor ovarian function during the premenopausal years and CHD risk is also difficult to ascertain in women due to the double challenge of characterizing ovarian function, and detecting an adequate number of clinical CHD events. However, La Vecchia reported that women with a history of irregular menstrual cycles are at increased risk for CHD (32). Ovarian hormones (particularly estradiol) are also associated with the function of the coronary arteries. In response to neuroendocrine signals, cor- onary arteries either dilate or constrict to modulate the flow of blood to the heart. Inappropriate coron- ary artery constriction, or vasospasm, early in life may change flow dynamics, injuring the epithelium and exacerbating atherosclerosis. Coronary vasos- pasm later in life in the presence of exacerbated atherosclerosis may increase the likelihood of my- ocardial infarction. In cynomolgus monkeys, the coronary arteries of normal cycling females dilate in response to acetylcholine infused directly into the coronary artery, whereas those of ovariectomized females constrict. The dilation response can be re- stored in ovariectomized females by administering estradiol, i.e. estrogen replacement therapy (33,34). The coronary arteries of dominant females with good ovarian function dilate in response to an infu- sion of acetylcholine, whereas those of subordinate females with poor ovarian function constrict in re- sponse to acetylcholine (35). Thus, female primates with poor ovarian function may be at increased CHD risk for two reasons: (1) impaired coronary artery function, and (2) increased atherogenesis. Ovarian function declines at menopause, particu- larly the production of estradiol and progesterone. Importantly, clinically detectable events occur most frequently during and after the menopausal decline in ovarian function. Thus, the impact of premenopausal ovarian function on CHD risk may be temporally separate from the clinical manifesta- tion of CHD. However, atherogenesis is a dynamic process that occurs over a lifetime. We hypothesize that atherogenesis during young and middle adult- hood may be accelerated among socially stressed women. These women enter the menopausal years with exacerbated atherosclerosis. During the estro- gen-deficient menopausal years, exacerbated atherosclerosis, combined with a more atherogenic lipid profile and increased likelihood of coronary vasospasm, result in increased CHD among women who experienced excessive premenopausal social stress. Social Status, Social Stress, and Depression Social stress is believed to precipitate depression (36—40) Unfortunately, depressive disorders are prevalent and the rate of occurrence is increasing (41). The results of several studies suggest that low social status is associated with increased risk of depression, although the nature of the relationship is unclear (42,43). In one prospective study in which low social status predicted first onset of major de- pressive disorder, a lack of social support (social isolation) appeared to mediate this relationship, at least in part (44). Thus, social support may reduce risk of depression following stressful life events (45,46). 205SOCIAL STRESS IN PRIMATES Figure 15.3 The effects of low social status on the prevalence of behavioral depression in female monkeys. (Based on data from Shively et al. (47)) The hypothesis that social subordination is stressful, and results in a depressive response in some individuals, was examined in the following experiment. Forty-eight adult female monkeys were fed an atherogenic diet, housed in small social groups, and social status was altered in half of the animals such that half of the subordinates became dominant, and half of the dominants became subor- dinate (Figure 15.3). Current subordinates hypersecreted cortisol, were insensitive to negative feedback, and had sup- pressed reproductive function. Current subor- dinates received more aggression, engaged in less affiliation, and spent more time alone than domi- nants. Furthermore, they spent more time fearfully scanning the social environment and displayed more behavioral depression than dominants. Cur- rent subordinates with a history of social subordi- nation were preferentially susceptible to a behav- ioral depression response. The results of this experiment confirm that the stress of social subordi- nation causes hypothalamic-pituitary-adrenal and ovarian dysfunction, and support the hypothesis that chronic, low-intensity social stress may result in depression in susceptible individuals (15,47). Interim Summary Low social status in female primates is associated with worsened coronary artery atherosclerosis. These females are the recipients of hostility/aggres- sion, and they are also relatively socially isolated. Females with low social status are also preferen- tially susceptible to a depressive response to social stress, particularly if they have a history of social subordination. Social stress increases the risk of CHD and pre- cipitates bouts of depression in human beings. Low socioeconomic status is associated with increased risk of depression and CHD. The relationship be- tween socioeconomic status and health in human beings is linear; there is no apparent threshold. The upper class has better health than the upper middle class, and so on down the hierarchy. Risk of disease is increased even among relatively low social status employed individuals with adequate health care, nutrition, and shelter. Thus, the health gradient does not appear to be due to poverty, per se (48). Perhaps the reason low social status is associated with increased risk of disease in human beings is because low social status is stressful. Like the mon- keys, human primates with low social status have relatively little control over their lives, and low control is a source of chronic stress that could en- gender physiological responses that are deleterious to health. REGIONAL ADIPOSITY AND CORONARY ARTERY ATHEROSCLEROSIS IN FEMALES We examined the relationship between social status, social stress, and central obesity in a series of studies of social group-living cynomolgus monkeys. In all of the experiments discussed below, adult monkeys were fed a moderately atherogenic diet that contained between 0.25 and 0.39 mg choles- terol/calorie and 40% of calories from fat (primarily saturated fat). These monkeys were housed in small social groups of four to six animals of the same gender. The initial investigation of regional adiposity and coronary artery atherosclerosis was a retrospective necropsy study of 36 adult female cynomolgus mon- keys (49). Whole body and regional adiposity were determined using anthropometric measurements. Whole body adiposity did not predict the extent of coronary artery atherosclerosis. However, the rela- tive amount of subcutaneous fat deposited on the 206 INTERNATIONAL TEXTBOOK OF OBESITY trunk (estimated by the ratio of subscapular:triceps skinfold thickness) versus the periphery was asso- ciated with coronary artery atherosclerosis extent. Females in the top half of the distribution of sub- scapular:triceps skinfold ratio had more than three times as much coronary artery atherosclerosis than females in the lower half of the distribution (49). REGIONAL ADIPOSITY AND METABOLIC ABERRATIONS Female cynomolgus monkeys with high central fat have higher glucose and insulin concentrations in an intravenous glucose tolerance test than females with relatively low central fat. They also have high- er blood pressure and total plasma cholesterol con- centrations, and lower HDL cholesterol concentra- tions compared to low central fat females (50). In women, central obesity has been linked with a metabolic syndrome consisting of impaired glucose tolerance, raised serum triglycerides and low levels of HDL cholesterol (51). SOCIAL SUBORDINATION AND REGIONAL ADIPOSITY To determine characteristics of subordinate females which increase their risk of coronary artery atheros- clerosis, whole body and regional adiposity were evaluated using anthropometric measurements in 75 adult female cynomolgus monkeys (52,53). Sub- ordinate females were more likely than dominants to be in the top half of the distribution of the sub- scapular:triceps skinfold ratio. This suggested the possibility of a relationship between stress and pat- terns of fat distribution that is associated with in- creased coronary artery atherosclerosis in monkeys and increased risk of coronary heart disease in women. Since that observation, we have attempted to further our understanding of the potential rela- tionship between stress and fat distribution. SOCIAL STRESS AND REGIONAL ADIPOSITY IN MALES Since truncal fat patterns are associated with an- drogenic hormone profiles, it is possible that the androgenic fat distribution pattern observed more frequently in social subordinates is due to ovarian dysfunction. To begin to address this possibility, the relationship between stress and fat distribution pat- terns was studied in male monkeys. Coronary ar- tery atherosclerosis is exacerbated in male cyno- molgus monkeys when their social groups are repeatedly disrupted. Social disruption has been achieved in several experiments by altering the con- stituency of social groups frequently (e.g. every 4 weeks) for a 2-year period. Generally, the monkeys respond to alterations in group membership by in- creased aggression and decreased affiliation (54). Thus, repeated social reorganization was used as the stressor in the following study of males. The monkeys were assigned to treatment groups using a method of stratified randomization that matched the groups for pretreatment plasma cho- lesterol concentrations. Pretreatment anthropo- metric measures were used to control for small (non-significant) differences in adiposity that were present prior to treatment. Computed tomography was used to measure intra-abdominal and subcu- taneous abdominal fat in forty monkeys and re- gional skinfold thicknesses were also measured (55). Males that lived in the stress condition produced by repeated social reorganization had significantly higher ratios of intra-abdominal:subcutaneous (IA: SQ) abdominal fat (56). This experiment provides important evidence supporting the hypothesis that social stress can al- ter regional fat deposition. The stressor was ma- nipulated by the experimenter rather than resulting from social group living, as in the previous observa- tion of an association between social status and regional fat deposition. These findings also indicate that stress can alter fat distribution patterns inde- pendent of ovarian function; however, the mechan- ism(s) that might relate these two factors remains to be determined. MECHANISMS MEDIATING THE RELATIONSHIP BETWEEN SOCIAL STRESS AND REGIONAL ADIPOSITY To identify potential mechanisms through which social stress might alter fat deposition patterns, a study was recently completed in which behavior, the function of the hypothalamic-pituitary-adrenal 207SOCIAL STRESS IN PRIMATES Table 15.1 Associations between abdominal fat distribution and behavioral characteristics of female monkeys IS: SQ Low High P % time being groomed 12(1.3) 8(1.5) 0.07 % time grooming 13(1.8) 7.5(0.8) 0.03 % time alone vigilant scan 36(2.2) 43(2.8) 0.07 % time alone 45(2.6) 54(3.4) 0.06 % mild aggression—attacker 31(6.3) 13(4.5) 0.05 % mild aggression—victim 12(3.6) 46(9.5) 0.001 % severe aggression—attacker 19(3.5) 17(5.5) 0.75 % severe aggression—victim 11(3.8) 31(9.5) 0.03 Social status (0 : Subordinate, 1 : Dominant) 0.6(0.1) 0.3(0.1) 0.002 IA: SQ, Intra-abdominal to subcutaneous abdominal fat ratio as measured using computed tomography. Figure 15.4 Association between abdominal fat distribution and heart rate in female monkeys. (Heart rates were recorded 2 months and 24 months following social group formation.) IA: SQ, Intra-abdominal to subcutaneous abdominal fat ratio as measured using computed tomography; HR, heart rate in beats per minute (bpm). ) Low IA: SQ;  high IA: SQ Figure 15.5 Dexamethasone suppression test. Relationship be- tween insensitivity to cortisol negative feedback and abdominal fat distribution. Females with low IA: SQ intra-abdominal to subcutaneous fat reduce cortisol secretion by 79%, whereas those with high IA: SQ abdominal fat reduce cortisol secretion by 54% (:0.05). IA: SQ, intra-abdominal to subcutaneous ab- dominal fat ratio as measured using computed tomography. White line, low IA: SQ; solid line, high IA: SQ axis, and the sympathetic nervous system were characterized in female cynomolgus monkeys. Ab- dominal fat mass was characterized by computed tomography as previously described (49,55). The monkeys lived in their social groups for 2  years, and social behavior was recorded throughout this time period. Females above the mean of the ratio of IA: SQ abdominal fat mass were compared to fe- males below the mean. Females with high IA: SQ abdominal fat ratios spent less time in affiliative social interaction, were more frequently the victims of aggression, and were socially subordinate compared to females with low IA: SQ abdominal fat ratios (Table 15.1). There was also a modest correlation between behavioral depression and the IA: SQ ratio (Spear- man’s rho : 0.26, P : 0.05, 1-tailed test), suggest- ing that females with relatively greater amounts of intra-abdominal fat were more likely to display be- havioral depression. Heart rate, a non-invasive in- dicator of sympathetic nervous system activity, was measured while the animals were in their social groups, using a telemetry system, from 15:00 h to 8:00 h the following day for three consecutive days. Heart rates of these animals are generally lowest at night, increase during the time of day when there is the most activity in their building, and decrease in the afternoon after the activity level in the building declines. Two months following the formation of social groups, there were no differences in high ver- sus low IA:SQ females. However, by 24 months, differences between these groups had emerged. The heart rates of all females were similarly elevated during the day; however, in the afternoon and night, heart rates of the females in the high IA: SQ ab- dominal fat group were higher than those in the low group (P : O 0.05; Figure 15.4). Hypothalamic-pituitary-adrenal (HPA) function was assessed using a dexamethasone suppression test. Suppression of serum cortisol in response to dexamethasone was greater in females in the lower 208 INTERNATIONAL TEXTBOOK OF OBESITY half of the distribution of IA: SQ abdominal fat mass (P : 0.05; Figure 15.5). This observation sug- gests that the central regulatory areas of the HPA axis of females with a relatively low IA: SQ ratio are more sensitive to circulatory cortisol concentra- tions than those with relatively high IA:SQ. Taken together, these data suggest that females with rela- tively greater amounts of visceral fat are also char- acterized by behavioral and physiological at- tributes indicative of chronic stress. Furthermore, the sympathetic nervous system and the HPA axis may mediate the relationship between social stress and regional adiposity. Our findings in cynomolgus monkeys support the hypothesis proposed by some that stress and a hypersensitive HPA axis are cen- tral abnormalities in abdominal obesity of human beings (51). SUMMARY In primates, abdominal obesity is associated with low social status, the metabolic syndrome, and in- creased risk of morbidity and mortality due to de- pression and cardiovascular disease. Data from stu- dies of monkeys suggest that social stress may be an underlying cause. We hypothesize that the stress of social subordination or social instability causes in- creased sympathetic nervous and HPA function. The chronic stimulation of these two systems leads to increased blood pressure and heart rate, and imbalances in sex steroid production which result in injury to the artery wall, and deposition of fat in the viscera. Visceral fat depots in turn exacerbate the metabolic effects of stress. Some of these physiologi- cal stress responses affect the function of the brain, resulting in depression. ACKNOWLEDGEMENT The studies reported here were funded, in part, by grants HL-39789, HL-14164, and HL-40962 from the National Institutes of Health, National Heart, Lung, and Blood Institute, Bethesda, MD. REFERENCES 1. Brunner EJ, Marmot MG, NanchahalK, Shipley MJ, Stans- feld SA, Juneja M, Alberti KGMM. Social inequality in coronary risk: central obesity and the metabolic syndrome. Evidence from the Whitehall II study. Diabetologia 1997; 40: 1341—1349. 2. Wingard DL, Suarez L, Barrett-Connor E. The sex differen- tial in mortality from all causes and ischemic heart disease. Am J Epidemiol 1983; 117:19—26. 3. Vanecek R. Atherosclerosis of the coronary arteries in five towns. Bull WHO 1976; 53: 509—518. 4. Tejada C, Strong JP, Montenegro MR, Restropo C, Solberg LA. Distribution of coronary and aortic atherosclerosis by geographic location, race, and sex. Lab Invest 1968; 18: 509—526. 5. Hamm TE Jr, Kaplan JR, Clarkson TB, Bullock BC. 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Arteriosclerosis 1990; 10: 358—366. 54. Kaplan JR, Manuck SB, Clarkson TB, Lusso FM, Taub DM. Social status, environment, and atherosclerosis in cynomolgus monkeys. Arteriosclerosis 1982; 2: 359—368. 210 INTERNATIONAL TEXTBOOK OF OBESITY 55. Laber-Laird K, Shively CA, Karstaedt N, Bullock BC. As- sessment of abdominal fat deposition in female cynomolgus monkeys. Int J Obes 1991; 15: 213—220. 56. Jayo J, Shively CA, Kaplan JR, Manuck SB. Effects of exercise and stress on body fat distribution in male cynomol- gus monkeys. Int J Obes 1993; 17: 597—604. 211SOCIAL STRESS IN PRIMATES 16 Centralization of Body Fat Per Bjo¨ rntorp Sahlgrenska University Hospital, Go¨ teborg, Sweden INTRODUCTION Centralization of body fat stores has proven to be an index of several serious diseases and their precur- sor states, indicated by risk factors. Historically this is an observation which originates from anthropol- ogists in the early twentieth century. Kretschmer (1) noticed the difference in disease associations with different body build, mainly from the aspect of his own specialty, which was psychiatry. He observed that the pychnic type frequently suffered from gout, atherosclerotic disease and stroke, and he saw early signs of glucose intolerance as well as abnormal pharmacological reactions of the autonomic nerv- ous system in comparison with, particularly, the leptosomic body build type. Both these types were also different from the aspect of food intake, where the pychnic type increased more readily in body weight. Kretschmer made anthropometric measure- ments from which the waist-to-hip circumference ratio (WHR) can be calculated. Such calculations show that the pychnic type had a WHR which is well within the risk zone for disease, as recently suggested by the WHO (2). The pychnic type was also more prone to develop depressive symptoms while the leptosomic type often had a schizoid per- sonality. Jean Vague in Marseille (3) is another pioneer who already 50 years ago saw the differences be- tween gynoid and android obesity and the risk for complications in the latter. Vague was focusing mainly on adipose tissue distribution but also made observations on other diseases than obesity. All these sharp-sighted clinical observations have been confirmed and extended in modern science with more refined methods, as will be briefly re- viewed in this chapter. Centralization of body fat stores can be measured in a number of ways. The gold standard methods for obtaining absolute masses of various body fat stores are the imaging techniques. These methods are, however, complicated and expensive to use in epi- demiological work, where simpler surrogate measurements have to be employed. Such methods include skinfolds, which, however, do not measure intra-abdominal fat masses. Various circumference measurements such as waist circumference or the WHR provide an estimate of internal fat masses. The WHR has probably been somewhat better an- chored in prospective studies of disease than the waist circumference, although the latter is slightly easier to measure. The abdominal sagittal diameter seems to provide the most accurate estimation of the important visceral, intra-abdominal fat masses (4). Utilizing such measurements, it has now become increasingly clear that body fat centralization is a powerful index of prevailing previously established risk factors for disease such as insulin resistance, dyslipidaemia and hypertension, is found with high prevalence in already established disease, and is a powerful independent risk factor for disease in pros- pective studies. The abnormalities associated with body fat centralization span a wide range of somatic diseases in metabolism and energy intake, such as obesity, cardiovascular and cerebrovascular diseases. Furthermore, respiratory, haematological International Textbook of Obesity. Edited by Per Bjo¨ rntorp. © 2001 John Wiley & Sons, Ltd. International Textbook of Obesity. Edited by Per Bjorntorp. Copyright © 2001 John Wiley & Sons Ltd Print ISBNs: 0-471-988707 (Hardback); 0-470-846739 (Electronic) and psychiatric diseases as well as cancer show associations with centralization of body fat. This is also the case for personality characteristics, alcohol abuse, socioeconomic and psychosocial handicaps. It is thus apparent that centralization of body fat embraces a large cluster of human life conditions, health and disease. Only from this wide array of conditions does it seem unlikely that central fat distribution could be a causative factor. It seems more likely that central- ization of body fat is an index of perturbations in profound, central regulation of several vital systems in the body. Such regulations usually have their origin in the hypothalamic—limbic areas of the brain, which regulate vital functions in endocrine, metabolic and haemodynamic systems via neuroen- docrine and autonomic signals to the periphery. This is orchestrated by the central nervous system into appropriate reactions to maintain homeostasis or allostasis. When various factors challenging these counterbalancing mechanisms become too se- vere, homeostasis or allostasis can no longer be maintained, and disease and disease symptoms will appear in the long run. In this chapter certain new developments within this area will be overviewed. The input into this research emanated originally from the obesity field, where Jean Vague’s pioneering work has attracted too little attention. Obesity will, however, only be briefly touched upon here, primarily with emphasis on novel findings. Instead an outlook into other diseases and conditions will be offered. Some, but not all, of these fields are related to obesity, suggest- ing that body fat centralization has a much more fundamental significance for human disease than only in the obesity field. By approaching various problems in biomedical research with epidemiological techniques on a population basis, it is possible to obtain a wide view on several diseases and their development, provided that a sufficient number of well-selected variables are examined. With this method many conditions can be analysed to search for potential pathogenetic pathways and generate hypotheses for further re- search. Selecting out only one phylogenetic charac- teristic for examination in case control studies limits the focus on the particular selected variable, for example obesity. In our research we have there- fore frequently based observations on epi- demiological studies to obtain a wider outlook on health problems. OBESITY. THE HYPOTHALAMIC-PITUITARY- ADRENAL (HPA) AXIS It must now be considered established that central, abdominal obesity is the malignant form of obesity. This condition seems to be associated with various perturbations of the function of the HPA axis. About one-quarter of a male population, selected at random, and all 52 years of age, have signs of an elevated diurnal cortisol secretion, associated with abdominally localized excess of body fat, measured with the sagittal, abdominal diameter, as well as signs of metabolic derangements, characteristic of the metabolic syndrome (5). It seems possible to explain the central fat accumulation as well as the metabolic derangements via effects of cortisol (6,7). The elevated cortisol secretion is seen most clearly when the endogenous activity of the HPA axis is most pronounced, that is before noon (Figure 16.1). During this period reports of perceived stress were also most prevalent (unpublished). This observation is in agreement with results of controlled animal experiments, where chronic stress facilitates this particularly active phase of HPA axis activity (8), and indicates that the men examined were exposed to a stressful environment not only during the day in their ordinary life when their cortisol secretion was measured, but also during a period preceding the examination. In about 10% of the population the HPA axis displays a depressed activity with less diurnal vari- ation, a ‘burn-out’ condition (see Figure 16.1). The cortisol secretion is about 75% of controls, and the secretion is again most perturbed during the high activity phase of the HPA axis. This is also in agree- ment with controlled animal experiments of chronic stress (9), and might be the end result of a develop- ment in stages from repeated stress challenges, as in the group of men mentioned above, to eventual burn-out. In spite of not being elevated, cortisol secretion in this condition is associated with central obesity and its well-known associated risk factors, including hy- pertension and elevated pulse rate. Interestingly, in this group secretions of testosterone and growth hormone are depressed (5), probably a consequence of the challenges on their central regulation by the HPA axis perturbations (10). Such a burned-out HPA axis has been observed 214 INTERNATIONAL TEXTBOOK OF OBESITY [...]... Metab 1994; 78: 151 5— 152 0 45 Tchernoff A, Labrie F, Belanger A, Prud’homme D, ´ Bouchard C, Tremblay A, Nadeau A, Despres JP Andros´ tane-3alpha, 17 -Diol glucuronide as a steroid correlate of visceral obesity in men J Clin Endocrinol Metab 1997; 82: 152 8— 153 4 46 Pasquali R, Casimirri F, De Iasio R, Mesini P, Boschi S, 238 47 48 49 50 51 52 53 54 55 56 57 58 59 60 INTERNATIONAL TEXTBOOK OF OBESITY Chierici... depression: relation to neurocircuitry and so- 224 44 45 46 47 48 49 50 51 52 53 54 55 56 INTERNATIONAL TEXTBOOK OF OBESITY matic consequences Proc Assoc Am Physicians 1999; 111: 22—34 Pratt LA, Ford DE, Crum RM, Arnenian HK, Fallo JJ, Eaton WW Depression, psychotropic medication, and risk of myocardial infarction Prospective data from the Baltimore ECA follow-up Circulation 1996; 94: 3123—3129 Eaton WW, Armenian... G-protein-coupled receptors that regulate feeding behavior Cell 1998; 92: 57 3 58 5 3 Smith SR The endocrinology of obesity Endocr Metab Clin NA 1996; 25: 921—942 4 Glass AR Endocrine aspects of obesity Med Clin NA 1989; 73: 139—160 5 Von Shoultz B, Carlstrom K On the regulation of sex-hormone-binding globulin A challenge of old dogma and outlines of an alternative mechanism J Steroid Biochem 1989; 32: 327—334... Metab 19 95; 80: 24 95 2498 Frystyk J, Vestbo E, Skjaerbaek C, Mogensen CE, Ørskov H Free insulin-like growth factors in human obesity Metabolism 19 95; 44 (Suppl) 37—44 Rasmussen MH, Frystyk J, Andersen T, Breum L, Christian- 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 sen JS, Hilsted J The impact of obesity, fat distribution and energy restriction on insulin like growth-factor-1 (IGF-1) IGF-binding... Hypothalamic-pituitary-adrenal axis activity and its relationship to the autonomic nervous system in women with visceral and subcutaneous obesity: effects of cortico-tropinreleasing factor/arginine-vasopressin test and of stress Metabolism 1996; 45: 351 — 356 239 85 Moyer AE, Rodin J, Grilo CM, Cummings N, Larson LM, Rebuffe-Scrive M Stress-induced cortisol response and fat ´ distribution in women Obes Res 1994; 2: 255 —262... a complex of factors, which include estrogens, iodothyronines and growth hormone (GH) as stimulating, and androgens and insulin as inhibiting factors (5) The net balance of this regulation is probably responsible for decreased SHBG con- 226 INTERNATIONAL TEXTBOOK OF OBESITY Table 17.2 Main alterations of the hypothalamic-pituitary-gonadal axis in obese women Condition Alterations Effect of obesity on... 83: 1 853 —1 859 Weaver JU, Kopelman PG, McLoughlin L, Forsling MI, Grossman A Hyperactivity of the hypothalamic-pituitaryadrenal axis in obesity: a study of ACTH, AVP, -lipotropin and cortisol responses to insulin-induced hypoglycemia Clin Endocrinol (Oxf) 1993; 39: 3 45 350 Pasquali R, Anconetani B, Chattat, Biscotti M, Spinucci G, Casimirri F, Vicennati V, Carcello A, Morselli-Labate AM Hypothalamic-pituitary-adrenal... pothalamic-pituitary-adrenal axis activity, testosterone, insulin-like growth factor I and abdominal obesity with me- 57 58 59 60 61 62 63 64 65 66 tabolism and blood pressure in men Int J Obes Relat Metab Disord 1998; 22: 1184—1196 Lapidus L, Helgesson O, Merck C, Bjorntorp P Adipose ¨ tissue distribution and female carcinomas A 12 year followup of the participants in the population study of women... various perturbations of the function of the HPA axis About one-quarter of a male population, selected at random, and all 52 years of age, have signs of an elevated diurnal cortisol secretion, associated with abdominally localized excess of body fat, measured with the sagittal, abdominal diameter, as well as signs of metabolic derangements, characteristic of the metabolic syndrome (5) It seems possible... after dietary weight loss J Clin Endocrinol Metab 1997; 82: 55 6 56 0 38 Zumoff B, Strain G, Miller LK, Rosner W, Senie R, Seres D, Rosenfield RS Plasma free and non-sex-hormone-bindingglobulin-bound testosterone are decreased in obese men in proportion to their degree of obesity J Clin Endo-crinol Metab 1990; 71: 929—931 39 Tchernoff A, Despres J-P, Belanger A, Dupont A, ´ ´ Prud’homme D, Moorjani S, Lupien . in cynomolgus monkeys. Arteriosclerosis 1982; 2: 359 —368. 210 INTERNATIONAL TEXTBOOK OF OBESITY 55 . Laber-Laird K, Shively CA, Karstaedt N, Bullock BC. As- sessment of abdominal fat deposition in female. essen- tially inactive metabolite excreted in the urine. The other system is the 11-hydroxysteroid dehyd- 216 INTERNATIONAL TEXTBOOK OF OBESITY rogenases (HSD), which consist of the HSD1, con- verting. 138—1 45. 51 . Rosmond R, Lapidus L, Bjo¨ rntorp P. The influence of occu- pational and social factors on obesity and body fat distribu- tion in middle-aged men. Int J Obes 1996; 20: 59 9—607. 52 .