Professional Documents
Culture Documents
Mcewen & Seeman Allostatic Load
Mcewen & Seeman Allostatic Load
Mcewen & Seeman Allostatic Load
cDivision
ABSTRACT: Stress is a condition of human existence and a factor in the expression of disease. A broader view of stress is that it is not just the dramatic stressful events that exact their toll but rather the many events of daily life that
elevate activities of physiological systems to cause some measure of wear and
tear. We call this wear and tear allostatic load, and it reflects not only the
impact of life experiences but also of genetic load; individual habits reflecting
items such as diet, exercise, and substance abuse; and developmental experiences that set life-long patterns of behavior and physiological reactivity (see
McEwen1). Hormones associated with stress and allostatic load protect the
body in the short run and promote adaptation, but in the long run allostatic
load causes changes in the body that lead to disease. This will be illustrated for
the immune system and brain. Among the most potent of stressors are those
arising from competitive interactions between animals of the same species,
leading to the formation of dominance hierarchies. Psychosocial stress of this
type not only impairs cognitive function of lower ranking animals, but it can
also promote disease (e.g. atherosclerosis) among those vying for the dominant
position. Social ordering in human society is also associated with gradients of
disease, with an increasing frequency of mortality and morbidity as one descends the scale of socioeconomic status that reflects both income and education. Although the causes of these gradients of health are very complex, they
are likely to reflect, with increasing frequency at the lower end of the scale, the
cumulative burden of coping with limited resources and negative life events
and the allostatic load that this burden places on the physiological systems involved in coping and adaptation.
INTRODUCTION
There are gradients of health, when groups of people are classified according to
their socioeconomic status, that reflect both income and level of education. The poor
suffer earlier mortality and worse health, on the average, than the middle class,
which, in turn, is not as healthy as those who are wealthier and/or better educated.
aAddress
31
Attempts to explain these gradients on the basis of access to health care or such behaviors as smoking have failed to explain the gradient.2,3 Instead there is a need to
understand more comprehensively how various aspects of life impact collectively on
health, involving such factors as living environment, work, relationships, community, and knowledge and practice of health-promoting or health-damaging behaviors
including diet and exercise. In order to do this, we must move from groups to individuals and understand how behavior and biology interact.
Often, we use the word stress to refer to these biological factors, but this is an
oversimplification because they are more than stress and include many aspects of
lifestyle and daily experience and behavior, including the adjustments to the circadian lightdark cycle. Moreover, the widespread use of the term stress in popular
culture has made this word an ambiguous term to describe the ways in which the
body copes with psychosocial, environmental, and physical challenges. Thus we
have been in search of a more comprehensive term for the role of biological mediators in adaptation and maladaptation of the individual to the circumstances of life.
32
33
FIGURE 2. Allostasis in the autonomic nervous system and the hypothalamicpituitaryadrenal axis.
Allostatic systems respond to stress (upper panel) by initiating the adaptive response, sustaining it until the stress
ceases, and then shutting it off (recovery). Allostatic responses are initiated
(lower panel) by an increase in circulating catecholamines from the autonomic
nervous system and glucocorticoids
from the adrenal cortex. This sets into
motion adaptive processes that alter the
structure and function of a variety of
cells and tissues. These processes are
initiated via intracellular receptors for
steroid hormones, plasma membrane receptors, and second messenger systems
for catecholamines. Cross-talk between
catecholamines and glucocorticoid receptor signaling systems can occur (see
text). (Reprinted from McEwen 1 by permission from the New England Journal
of Medicine.)
34
challenges and adverse environments) that is related to how inefficient the response
is, or how many challenges an individual experiences (i.e., a lot of stressful events).
Thus allostatic load is more than chronic stress and encompasses many aspects of
an individuals life that affect the regulation and level of the mediators of allostasis.
Among the many factors that contribute to allostatic load are genes and early development, as well as learned behaviors reflecting life style choices of diet, exercise,
smoking, and drinking. All of these factors influence the reactivity of the systems
that produce the physiological stress mediators. Thus allostatic load reflects, in part,
genetically or developmentally programmed inefficiency in handling, the normal
challenges of daily life related to the sleepwake cycle and other daily experiences,
as well as the adverse physiological consequences of a fat-rich diet, drinking, or
smoking.
Many of the same considerations apply to behavioral, as opposed to physiological, responses to challenge, and there are also protective and damaging aspects to
ones behavior. Individuals can act to increase or decrease further risk for harm or
diseasefor example, antisocial responses such as hostility and aggression versus
cooperation and conciliation; risk-taking behaviors such as smoking, drinking, and
physical risk-taking versus self-protection; poor diet and health practices versus
good diet, exercise, etc. The linkage of allostasis and allostatic load probably applies to behavioral responses as well to physiological responses to challenge insofar
as the behavioral response, such as smoking or alcohol consumption, may have at
least perceived adaptive benefits in the short run but produce damaging effects in the
long run.
35
the face of job stress or the failure to shut off blood pressure surges efficiently accelerates atherosclerosis and synergizes with metabolic hormones to produce Type II
diabetes, and this constitutes a type of allostatic load (see McEwen1). Closely related to this is the role of adrenal steroids in metabolism. Whereas adrenal steroids promote allostasis by enhancing food intake and facilitating the replenishment of energy
reserves, the overactivity of this system involving repeated HPA activity in stress or
elevated evening, cortisol leads to allostatic load in terms of insulin resistance, accelerating progression towards Type II diabetes, including abdominal obesity, atherosclerosis, and hypertension.9,10
In the brain, actions of adrenal steroids and catecholamines that are related to allostasis include promoting retention of memories of emotionally charged events,
both positive and negative. Yet, overactivity of the HPA axis together with overactivity of the excitatory amino acid neurotransmitters promotes a form of allostatic load,
consisting of cognitive dysfunction by a variety of mechanisms that involve reduced
neuronal excitability, neuronal atrophy, and, in extreme cases, death of brain cells,
particularly in the hippocampus.11,12
For the immune system, adrenal steroids promote allostasis together with catecholamines by promoting trafficking (i.e., movement) of immune cells to organs
and tissues where they are needed to fight an infection or other challenge, and they
also modulate the expression of the hormones of the immune systems, the cytokines
and chemokines.13 With chronic overactivity of these same mediators, allostatic load
results, consisting of immunosuppressive effects when these mediators are secreted
chronically or not shut off properly.13 Yet, some optimal levels of these mediators is
required to maintain a functional balance within the competing forces of the immune
system, and the absence of sufficient levels of glucocorticoids and catecholamines
allows other immune mediators to overreact and increases the risk of autoimmune
and inflammatory disorders.14 Therefore, an inadequate response of the HPA axis
and autonomic nervous system is another type of allostatic load, in which the disregulation of other mediators, normally contained by cortisol and catecholamines, is a
primary factor in a disorder.
Thus, allostatic load may be subdivided into at least four subtypes, as summarized in FIGURE 3. The first type is simply too much stress in the form of repeated,
novel events that cause repeated elevations of stress mediators over long, periods of
time. For example, the amount and frequency of economic hardship predicts decline
of physical and mental functioning as well as increased mortality.15 Yet not all types
of allostatic load deal with chronic stress. A second type of allostatic load depicted
in FIGURE 3 involves a failure to habituate or adapt to the same stressor. This leads
to the overexposure to stress mediators because of the failure of the body to dampen
or eliminate the hormonal stress response to a repeated event. An example of this is
the finding that repeated public speaking, challenges, in which most individuals habituated their cortisol response, led a significant minority of individuals to fail to habituate and continue to show cortisol response.16
A third and related type of allostatic load, also depicted in F IGURE 3, involves the
failure to shut off either the hormonal stress response or to display the normal trough
of the diurnal cortisol pattern. One example of this is blood pressure elevations in
work-related stress which turn off slowly in some individuals with a family history
of hypertension.17 Another example of perturbing the normal diurnal rhythm is that
36
FIGURE 3. Four types of allostatic load. The top panel illustrates the normal allostatic response, in which a response is initiated by a stressor, sustained for an appropriate interval, and then turned off. The remaining panels illustrate four conditions that lead to
allostatic load: (1) repeated hits from multiple novel stressors, (2) lack of adaptation,
(3) prolonged response due to delayed shut down, and (4) inadequate response leading to
compensatory hyperactivity of other mediators (e.g., inadequate secretion of glucocorticoid,
resulting in increased levels of cytokines that are normally counterregulated by glucocorticoids). Figure drawn by Dr. Firdaus Dhabhar, The Rockefeller University, New York. (Reprinted from McEwen 1 by permission from the New England Journal of Medicine.)
37
38
39
40
for the secondary and tertiary outcomes, we must become more organ and disease
specific!
41
42
Refs. 4248). Moreover, experiences in childhood have other, deleterious consequences: for example, a history of sexual and physical abuse in childhood is a risk
factor not only for posttraumatic stress disorder but also for hippocampal atrophy
and cognitive impairment in adulthood (see Bremner48). As noted above, in clinical
studies, new evidence for the consequences of child abuse and dysfunction of the
family in early life points to substantial increases in substance abuse, depression, and
suicide, as well as sexual promiscuity and in increased incidence of heart disease,
cancer, chronic lung disease, extreme obesity, skeletal fractures, and liver disease.40
Abuse and neglect during early childhood also links to the neurochemical imbalances that are associated with low serotonin and risk for hostility, aggression, substance
abuse, and suicide, as discussed earlier in this section. Studies in infrahuman primates have shown that early maternal deprivation reduces brain serotonin levels and
increases alcohol preference and aggressive behavior and decreases affiliative
behaviors, thus increasing the risk for elevated allostatic load50 (for discussion see
Higley et al.51).
Evidence from human studies indicates similar patterns of altered physiological
regulation in children exposed to risky families (i.e., families characterized by aggression, lack of warmth, or over/under-regulation). In these latter studies, children
from such families exhibit dysregulated HPA axis activity, characterized primarily
by higher levels of activity (see Repetti et al.41). There is also evidence suggesting
dysregulation of serotonergic function, especially among children exposed to
abuse52 and to deficient nurturing.53 To the extent that such dysregulations are experienced chronically by these children, they would be hypothesized to contribute to
more rapid cumulation of allostatic load and its resulting health risks.
In general, the health effects of trauma and other childhood adversities are very
broad and do not appear to be specific for any one type of psychiatric or other
disorder40,54; the breadth and strength of the effects of such trauma is reminiscent of
the broad systemic effects of alterations of the responsiveness of physiological mediators that is embodied in the concept of allostatic load.
43
Western countries. (See Refs. 2, 3, and 55; also chapters by Marmot, Adler, and others in this volume.) It should be emphasized that these are true gradients, operating
over the full range of SES and not just a phenomenon of the poorest or lowest end
of the scale. Indeed, the measurement of allostatic load, involving secondary outcome measures such as waisthip ratio55 and fibrinogen32 has revealed gradients that
parallel the gradients for cardiovascular disease and mortality, indicating that the
further application of these measures to different populations should enrich our
knowledge of the underlying biological risk factors. Analysis of data from a longitudinal cohort study in Finland has also shown that biological risk factors account
for at least part of the association between lower SES and mortality risk, since
previously significant SES differences in risks are reduced to nonsignificance with
controls for a range of biological parameters including fibrinogen, lipids, blood pressure, glucose, and BMI.57
Although it is important to measure allostatic load as a function of SES in different populations, we continue to look for social and cultural factors that have an
impact on individual health and provide insights into the driving forces behind
allostatic load and poorer health. For example, economic hardship, defined in purely
economic terms, has been shown independently of SES gradients to compromise
health, including cognitive and physical function and mental health (see Lynch
et al.15), although there has been little attention to possible physiological mediators
of these relationships. And social upheaval in a society is also associated with poorer
health. The collapse of communism resulted in worse health in Eastern Europe,
and particularly in Russia, between 1989 and 1993; and behavioral problems
alcoholism, suicide, homicide, and cardiovascular diseaseaccounted for much of
the increased mortality (see Refs. 5860).
CONCLUSIONS
Allostatic load appears to be a useful construct for conceptualizing how wear
and tear and increased morbidity and mortality are caused over long, time intervals,
not only by the more dramatic stressful life events but also by the many events of
daily life that elevate activities of physiological systems. Allostatic load reflects the
impact not only of life experiences but also of genetic load; individual habits reflecting items such as diet, exercise, and substance abuse; and developmental experiences
that set life-long patterns of behavior and physiological reactivity. All of these factors influence the temporal patterning and efficiency of turning on and turning off the
hormonal mediators of stress, primarily the catecholamines and glucocorticoids.
These hormones protect the body in the short run and promote adaptation, but in the
long run allostatic load causes changes in the body that lead to disease. Factors in
early life that increase allostatic load include childhood abuse and neglect.
Throughout life, the most potent influences arise from competitive interactions
between animals of the same species, leading to the formation of dominance hierarchies. Psychosocial stress of this type not only impairs cognitive function of lower
ranking animals, but it can also promote disease (e.g., atherosclerosis) among those
vying for the dominant position. Social ordering in human society is also associated
with gradients of disease, with an increasing frequency of mortality and morbidity
44
as one descends the scale of socioeconomic status that reflects both income and education. Social ordering in humans may also be associated with gradients of such
factors as early life abuse and neglect, as well as prenatal influences that increase the
risk for low birthweight, which is itself a risk factor for obesity and cardiovascular
disease. Although the causes of these gradients of health are very complex, they are
likely to reflect, with increasing frequency at the lower end of the scale, the cumulative burden of coping with limited resources and negative life events and the allostatic load that this burden places on the physiological systems involved in coping and
adaptation.
REFERENCES
1. M CE WEN, B.S. 1998. Protective and damaging effects of stress mediators. N. Engl. J.
Med. 338: 171179.
2. A DLER, N., W.T. B OYCE, M. C HESNEY, S. F OLKMAN & L. S YME. 1993. Socioeconomic
inequalities in health: no easy solution. J. Am. Med. Assoc. 269: 31403145.
3. A DLER, N.E., T. B OYCE, M.A. C HESNEY, S. C OHEN, S. F OLKMAN, R.L. K AHN &
L.S. S YME. 1994. Socioeconomic status and health: the challenge of the gradient.
Am. Psychol. 49: 1524.
4. K IRSCHBAUM, C., B.M. K UDIELKA, J. G AAB, N.C. S CHOMMER & D.H. H ELLHAMMER.
1999. Impact of gender, menstrual cycle phase and oral contraceptive use on the
activity of the hypothalamopituitaryadrenal axis. Psychosom. Med. 61: 154162.
5. S TERLING, P. & J. E YER. 1988. Allostasis: a new paradigm to explain arousal pathology. In Handbook of Life Stress, Cognition and Health. S. Fisher & J. Reason, Eds.:
629649. John Wiley & Sons, New York.
6. M CE WEN, B.S. & E. S TELLAR. 1993. Stress and the individual: mechanisms leading to
disease. Arch. Int. Med. 153: 20932101.
7. M ANUCK, S.B., J.R. K APLAN, M.R. A DAMS & T.B. C LARKSON. 1995. Studies of psychosocial influences on coronary artery atherosclerosis in cynomolgus monkeys.
Health Psychol. 7: 113124.
8. M ANUCK, S.B., J.R. K APLAN, M.F. M ULDOON, M.R. A DAMS & T.B. C LARKSON. 1991.
The behavioral exacerbation of atherosclerosis and its inhibition by propranolol.
In Stress, Coping and Disease. P.M. McCabe, N. Schneiderman, T.M. Field &
J.S. Skyler, Eds.: 5172. Lawrence Erlbaum Associates, Hove and London.
9. B RINDLEY, D.N. & Y. R OLLAND. 1989. Possible connections between stress, diabetes,
obesity, hypertension and altered lipoprotein metabolism that may result in atherosclerosis. Clin. Sci. 77: 453461.
10. B JORNTORP, P. 1990. Editorial: Portal adipose tissue as a generator of risk factors for
cardiovascular disease and diabetes. Atherosclerosis 10: 493496.
11. M CE WEN, B.S. 1997. Possible mechanisms for atrophy of the human hippocampus.
Mol. Psychiatry 2: 255262.
12. M CE WEN, B.S. 1999. Stress and hippocampal plasticity. Annu. Rev. Neurosci. 22:
105122.
13. M CE WEN, B.S., C.A. B IRON, K.W. B RUNSON, K. B ULLOCH, W.H. C HAMBERS,
F.S. D HABHAR, R.H. G OLDFARB, R.P. K ITSON, A.H. M ILLER, R.L. S PENCER &
J.M. W EISS. 1997. Neuralendocrineimmune interactions: the role of adrenocorticoids as modulators of immune function in health and disease. Brain Res. Rev. 23:
79133.
14. S TERNBERG, E.M. 1997. Neural-immune interactions in health and disease. J. Clin.
Invest. 100: 26412647.
15. L YNCH, J.W., G.A. K APLAN & S.J. S HEMA. 1997. Cumulative impact of sustained economic hardship on physical, cognitive, psychological, and social functioning. N.
Engl. J. Med. 337: 18891895.
45
16. K IRSCHBAUM, C., J.C. P RUSSNER, A.A. S TONE, 1. F EDERENKO, J. G AAB, D. L INTZ,
N. S CHOMMER & D.H. H ELLHAMMER. 1995. Persistent high cortisol responses to
repeated psychological stress in a subpopulation of healthy men. Psychosom. Med.
57: 468474.
17. G ERIN, W. & T.G. P ICKERING. 1995. Association between delayed recovery of blood
pressure after acute mental stress and parental history of hypertension. J. Hypertension 13: 603610.
18. V AN C AUTER, E., K.S. P OLONSKY & A.J. S CHEEN. 1997. Roles of circadian rhythmicity and sleep in human glucose regulation. Endocrinol. Rev. 18: 716738.
19. M ICHELSON, D., C. S TRATAKIS, L. H ILL, J. R EYNOLDS, E. G ALLIVEN, G. C HROUSOS &
P. G OLD. 1996. Bone mineral density in women with depression. N. Engl. J. Med.
335: 11761181.
20. S TERNBERG, E.M., J.M. H ILL & G.P. C HROUSOS. 1996. Inflammatory mediatorinduced hypothalamicpituitaryadrenal axis activation is defective in streptococcal
cell wall arthritis susceptible Lewis rats. Proc. Natl. Acad. Sci. 86: 23742378.
21. S EEMAN, T.E., B.H. S INGER, J.W. R OWE, R.I. H ORWITZ & B.S. M CE WEN. 1997. Price
of adaptationallostatic load and its health consequences: MacArthur studies of
successful aging. Arch. Intern. Med. 157: 22592268.
22. M CE WEN, B.S., R.R. S AKAI & R.L. S PENCER. 1993. Adrenal steroid effects on the
brain: versatile hormones with good and bad effects. In Hormonally-Induced
Changes in Mind and Brain. J. Schulkin, Ed.: 157189. Academic Press, San Diego.
23. Q UIRARTE, G.L., B. R OOZENDAAL & J.L. M CG AUGH. 1997. Glucocorticoid, enhancement of memory storage involves noradrenergic activation in the basolateral
amygdala. Proc. Natl. Acad. Sci. USA 94: 1404814053.
24. M AY, M., E. H OLMES, W. R OGERS & M. P OTH. 1990. Protection from glucocorticoid
induced thymic involution by dehydroepiandrosterone. Life Sci. 46: 16271631.
25. W RIGHT, B.E., J.R. P ORTER, E. B ROWNE & F. S VEC. 1992. Antiglucocorticoid action
of dehydroepiandrosterone in young obese Zucker rats. Int. J. Obesity 16: 579593.
26. A RANEO, B. & R. D AYNES. 1995. Dehydroepiandrosterone functions as more than an
antiglucocorticoid in preserving immunocompetence after thermal injury. Endocrinology 136: 393401.
27. M ORALES, A.J., J.J. N OLAN, J.C. N ELSON & S.S.C. Y EN. 1994. Effects of replacement
dose of dehydroepiandrosterone in men and women of advancing age. J. Clin. Endocrinol. Metab. 78: 13601367.
28. C AHILL, L., B. P RINS, M. W EBER & J.L. M CG AUGH. 1994. Beta-adrenergic activation
and memory for emotional events. Nature 371: 702704.
29. M INER, J.N., M.I. D IAMOND & K.R. Y AMAMOTO. 1991. Joints in the regulatory lattice:
composite regulation by steroid receptorAP I complexes. Cell Growth Differ. 2:
525530.
30. S IEGEL, G.J., B.W. A GRANOFF, R.W. A LBERS, S.K. F ISHER & M.D. U HLER. 1999.
Basic Neurochemistry. Sixth edit. Lippincott-Raven, New York.
31. Y AMADA, K., D.T. D UONG, D.K. S COTT, J.-C. W ANG & D.K. G RANNER. 1999.
CCAAT/Enhancer-binding protein is an accessory factor for the glucocorticoid
response from the cAMP response element in the rat phosphoenolpyruvate carboxykinase gene promoter. J. Biol. Chem. 274: 58805887.
32. M ARKOWE, H.L.J., M.G. M ARMOT, M.J. S HIPLEY, C.J. B ULPITT, T.W. M EADE,
Y. S TIRLING, M.V. V ICKERS & A. S ERNMENCE. 1985. Fibrinogen: a possible link
between social class and coronary heart disease. Br. Med. J. 291: 13121314.
33. L UPIEN, S.J., M.J. D EL EON, S. D E S ANTI, A. C ONVIT, C. T ARSHISH, N.P.V. N AIR,
M. T HAKUR, B.S. M CE WEN, R.L. H AUGER & M.J. M EANEY. 1998. Cortisol levels
during human aging predict hippocampal atrophy and memory deficits. Nature Neurosci. 1: 6973.
34. D HABHAR, F.S. & B.S. M CE WEN. 1996. Moderate stress enhances, and chronic stress
suppresses, cell-mediated immunity in vivo. Soc. Neurosci. 22: 536.3p1350.
(Abstr.).
35. D HABHAR, F. & B. M CE WEN. 1999. Enhancing versus suppressive effects of stress
hormones on skin immune function. Proc. Natl. Acad. Sci. USA 96: 10591064.
46
36. KIECOLT -GLASER , J.K., R. GLASER , S. GRAVENSTEIN , W.B. MALARKEY & J. SHERIDAN .
1996. Chronic stress alters the immune response to influenza virus vaccine in older
adults. Proc. Natl. Acad. Sci. USA 93: 30433047.
37. C OHEN, S., S. L INE, S.B. M ANUCK, B.S. R ABIN, E.R. H EISE & J.R. K APLAN. 1997.
Chronic social stress, social status, and susceptibility to upper respiratory infections
in nonhuman primates. Psychosomat. Med. 59: 213221.
38. C OHEN, S., D.A.J. T YRRELL & A.P. S MITH. 1991. Psychological stress and susceptibility to the common cold. N. Engl. J. Med. 325: 606612.
39. S EEMAN, T.E., B.S. M CE WEN, B.H. S INGER, M.S. A LBERT & J.W. R OWE. 1997.
Increase in urinary cortisol excretion and memory declines: MacArthur studies of
successful aging. J. Clin. Endocrinol. Metab. 82: 24582465.
40. F ELITTI, V.J., R.F. A NDA, D. N ORDENBERG, D.F. W ILLIAMSON, A.M. S PITZ,
V. E DWARDS, M.P. K OSS & J.S. M ARKS. 1998. Relationship of childhood abuse and
household dysfunction to many of the leading causes of death in adults. The adverse
childhood experiences (ACE) study. Am. J. Prev. Med. 14: 245258.
41. R EPETTI, R.L., S. T AYLOR & T S EEMAN. 1999. Risky families: family social environments and the mental and physical health of offspring. Submitted.
42. M EANEY, M., D. A ITKEN, H. B ERKEL, S. B HATNAGER & R. S APOLSKY. 1988. Effect of
neonatal handling of age-related impairments associated with the hippocampus. Science 239: 766768.
43. D ELLU, F., W. M AYO, M. V ALLEE, M. L EM OAL & H. S IMON. 1994. Reactivity to novelty during youth as a predictive factor of cognitive impairment in the elderly: a longitudinal study in rats. Brain Res. 653: 5156.
44. L IU, D., J. D IORIO, B. T ANNENBAUM, C. C ALDJI, D. F RANCIS, A. F REEDMAN,
S. S HARMA, D. P EARSON, P.M. P LOTSKY & M.J. M EANEY. 1997. Maternal care, hippocampal glucocorticoid receptors, and hypothalamicpituitaryadrenal responses to
stress. Science 277: 16591662.
45. L UPIEN, S., A.R. L ECOURS, 1. L USSIER, G. S CHWARTZ, N.P.V. N AIR & M.J. M EANEY.
1994. Basal cortisol levels and cognitive deficits in human aging. J. Neurosci. 14:
28932903.
46. W ADHWA, P.D., C.A. S ANDMAN, M. P ORTO, C. D UNKEL-S CHETTER & T.J. G ARITE.
1993. The association between prenatal stress and infant birth weight and gestational
age at birth: a prospective investigation. Am. J. 0b. Gyn. 169: 858865.
47. B ARKER, D.J.P. 1997. The fetal origins of coronary heart disease. Acta. Paediatr.
Suppl. 422: 7882.
48. W ADHWA, P.D., C.A. S ANDMAN, A. C HICZ- DEM ET & M. P ORTO. 1997. Placental CRH
modulates maternal pituitaryadrenal function in human pregnancy. Neuropeptides
Dev. Aging 814: 276281.
49. B REMNER, J.D., P. R ANDALL, E. V ERMETTEN, L. S TAIB, R.A. B RONEN, C. M AZURE,
S. C APELLI, G. M CC ARTHY, R.B. I NNIS & D.S. C HARNEY. 1997. Magnetic resonance
imaging-based measurement of hippocampal volume in posttraumatic stress disorder
related to childhood physical and sexual abusea preliminary report. Biol. Psychiatry 41: 2332.
50. H IGLEY, J.D., M.F. H ASERT, S.J. S UOMI & M. L INNOILA. 1991. Nonhuman primate
model of alcohol abuse: effects of early experience, personality, and stress on alcohol consumption. Proc. Natl. Acad. Sci. USA 88: 72617265.
51. H IGLEY, J.D., W.W. T HOMPSON, M. C HAMPOUX, D. G OLDMAN, M.F. H ASERT,
G.W. K RAEMER, J.M. S CANLAN, S.J. S UOMI & M. L INNOILA. 1993. Paternal and
maternal genetic and environmental contributions to cerebrospinal fluid monoamine
metabolites in Rhesus monkeys (Macaca mulatta). Arch. Gen. Psychiatry 50: 615
623.
52. K AUFMAN, J., B. B IRMAHER, J. P EREL, R.E. D AHL, S. S TULL, D. B RENT, L. T RUBNICK,
M. A L-S HABBOUT & N.D. R YAN. 1998. Serotonergic functioning in depressed
abused children: clinical and familial correlates. Biol. Psychiatry 44: 973981.
53. P INE, D.S., J.D. C OPLAN, G.A. W ASSERMAN, L.S. M ILLER, J.E. F RIED, M. D AVIES,
T.B. C OOPER, L. G REENHILL, D. S HAFFER & B. P ARSONS. 1998. Neuroendocrine
response to D,1-fenfluramine challenge in boys. Associations with aggressive behavior and adverse rearing. Arch. Gen. Psychiatry 54: 785789.
47
54. K ESSLER, R.C., C.G. D AVIS & K.S. K ENDLER. 1997. Childhood adversity and adult
psychiatric disorder in the US National Comorbidity Survey. Psychol. Med. 27:
11011119.
55. M ARMOT, M.G., G. D AVEY S MITH, S. S TANSFELD, C. P ATEL, F. N ORTH, J. H EAD,
I. W HITE, E. B RUNNER & A. F EENEY. 1991. Health inequalities among British civil
servants: the Whitehall 11 study. Lancet 337: 13871393.
56. B RUNNER, E.J., M. M ARMOT, K. N ANCHAHAL, M.J. S HIPLEY, S.A. S TANSFELD,
M. J UNEJA & K.G.M.M. A LBERTI. 1997. Social inequality in coronary risk: central
obesity and the metabolic syndrome. Evidence from the Whitehall 11 study. Diabetologia 40: 13411349.
57. L YNCH, J.W., G.A. K APLAN, R.D. C OHEN, J. T UOMILEHTO & J.T. S ALONEN. 1996. Do
cardiovascular risk factors explain the relation between socioeconomic status, risk of
all-cause mortality, cardiovascular mortality, and acute myocardial infarction? Am.
J. Epidemiol. 144: 934942.
58. B OBAK, M. & M. M ARMOT. 1996. EastWest mortality divide and its potential explanations: proposed research agenda. Br. Med. J. 312: 421425.
59. N OTZON, F.C., Y.M. K OMAROV, S.P. E RMAKOV, C.T. S EMPOS, J.S. M ARKS &
E.V. S EMPOS. 1998. Causes of declining life expectancy in Russia. JAMA 279: 793
800.
60. B OBAK, M., H. P IKHART, C. H ERTZMAN, R. R OSE & M. M ARMOT. 1998. Socioeconomic factors, perceived control and self-reported health in Russia. A crosssectional survey. Soc. Sci. Med. 47: 269279.