Psychosocial Factors That Influence Coronary Artery Atherosclerosis And Chd Risk In Female Monkeys

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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 dominants.

The distinguishing behavioral characteristics of subordinates are depicted in Figure 15.1. Subordinate 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 scanning appears to be to track and avoid dominants in order to avoid aggressive interactions. Subordinates also spend significantly more time alone than dominant females (13-15). Primates typically communicate non-verbally by touch, facial expressions and body language or postures. Although human primates also are able to communicate with language, they still rely heavily on non-verbal communication. 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 monkeys suggesting that social isolation increased coronary artery atherosclerosis and heart rate (16-18). Thus, it seems that subordinates are subject to hostility and have very little social support.

Physiological characteristics of subordinates that distinguish them from dominants include differences in measurements of adrenal function. Following dexamethasone suppression, the adrenal glands of subordinate females hypersecrete cortisol in response to an adrenocorticotropic hormone challenge, and are also relatively insensitive to cortisol

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 = frequency per hour; % time = percentage of time spent. (Based on data from Shively et al. (13,14))

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 = frequency per hour; % time = percentage of time spent. (Based on data from Shively et al. (13,14))

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 females (8). Progesterone concentrations are lower during the luteal phase, and estradiol concentrations are lower in the follicular phase of the menstrual cycles of subordinate females. Moderately low luteal phase progesterone concentrations indicate 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, subordinate females have poor ovarian function compared to dominants. Subordinate females with poor ovarian function have more coronary artery atherosclerosis than their dominant counterparts (Figure 15.2). Indeed, the coronary artery atherosclerosis 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 difficulties 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-

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 ovarian function; white bars = intact socially dominant females with good ovarian function. (Based on data from Hamm et al. (5), Adams et al. (8))

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 ovarian 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 reproductive function in female primates have been identified, suggesting that the stress-ovarian function impairment hypothesis is plausible from a physiological perspective. Activation of the hypothalamic-pituitary-adrenal axis, endogenous opioid pathways, 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, coronary arteries either dilate or constrict to modulate the flow of blood to the heart. Inappropriate coronary 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 restored 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 infusion of acetylcholine, whereas those of subordinate females with poor ovarian function constrict in response 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, particularly 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 manifestation of CHD. However, atherogenesis is a dynamic process that occurs over a lifetime. We hypothesize that atherogenesis during young and middle adulthood may be accelerated among socially stressed women. These women enter the menopausal years with exacerbated atherosclerosis. During the estrogen-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 depressive 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).

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 subordinate (Figure 15.3).

Current subordinates hypersecreted cortisol, were insensitive to negative feedback, and had suppressed reproductive function. Current subordinates received more aggression, engaged in less affiliation, and spent more time alone than dominants. Furthermore, they spent more time fearfully scanning the social environment and displayed more behavioral depression than dominants. Current subordinates with a history of social subordination were preferentially susceptible to a behavioral depression response. The results of this experiment confirm that the stress of social subordination 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/aggression, and they are also relatively socially isolated. Females with low social status are also preferentially 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 precipitates bouts of depression in human beings. Low socioeconomic status is associated with increased risk of depression and CHD. The relationship between 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 monkeys, human primates with low social status have relatively little control over their lives, and low control is a source of chronic stress that could engender physiological responses that are deleterious to health.

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