Convergent genetic modulation of the endocrine stress response involves polymorphic variations of 5-HTT, COMT and MAOA.

Highly prevalent stress-related disorders such as major depression (MD) are characterised by a dysregulation of the neuroendocrine system. Although heritability for these disorders is high, the role of genes in the underlying pathophysiology is poorly understood. Here, we show that polymorphic variations in genes coding for serotonin transporter (5-HTT), catechol-O-methyl transferase (COMT) and monoamine oxidase A (MAOA) as well as sex differences influence the regulation of hypothalamic-pituitary-adrenal (HPA)-axis response to acute psychological and endocrine challenges. In our sample, the effects of COMT on the release of adrenocorticotrophin hormone (ACTH) depend on the presence of the low-expression MAOA variant in the same individual. By including individuals varying in their degree of susceptibility to MD, we showed evidence of interactions between 5-HTT and MD susceptibility in baseline cortisol, and between MAOA and MD susceptibility in baseline ACTH measures, indicating a role for these genotypes in stable-state endocrine regulation. Collectively, these results indicate that the simultaneous investigation of multiple monoaminergic genes in interaction with gender have to be measured to understand the endocrine regulation of stress. These findings point towards a genetic susceptibility to stress-related disorders.

Free recall of pleasant words from recency positions is especially sensitive to acute administration of cortisol.

In a recent study we investigated the acute effects of cortisol administration in healthy male volunteers on free recall of pleasant, unpleasant, and neutral nouns using a between-subjects double-blind placebo-controlled design. The volunteers were administered 10 mg of hydrocortisone or placebo between 9:00 and 10:30. Two hours after administration of cortisol a decline in recall of neutral and pleasant words was found, while recall of unpleasant words did not change. These results are consistent with a possible inhibitory influence of cortisol on a prefrontal dopaminergic mechanism involved in approach and positivity bias. In this paper we first explain why this interpretation would predict recall of pleasant words from recency positions to be especially sensitive to cortisol administration. Comparing primacy and recency recall of pleasant and unpleasant words, there proved to be a selective decline in recall of pleasant recency words. These results did not appear to stem from differences in recall strategies between our groups of volunteers.

An exploratory study into the effect of group psychotherapy on cardiovascular and immunoreactivity to acute stress in breast cancer patients.

BACKGROUND: : Previous studies of cancer patients investigated the effect of psychological treatment on basal endocrine and immune values. Using a randomized experiment, we explored the effect of a 13-week experiential-existential group psychotherapy (EEGP) program on the reactivity to a speech task in breast cancer patients. We explored whether changes in cardiovascular and immune reactivity to a speech task over the 3-month period correlated with changes in psychological distress and emotional expression. METHODS: Patients who had been treated for early-stage breast cancer and who were diagnosed as having either positive axillary lymph nodes or distant metastases were randomly assigned to either EEGP or a waiting list control (WLC) condition. We continuously recorded heart rate (HR), diastolic (DBP) and systolic blood pressure (SBP) in response to the speech task before and after treatment. We also measured lymphocyte proliferation to pokeweed (PWM) and phytohemagglutinin (PHA), and natural killer cell activity (NKCA) as well as peripheral blood lymphocyte distributions in blood samples that were drawn before, during and after the speech task. RESULTS: Patients in EEGP had smaller increases in natural killer (NK) cells induced by the speech task after treatment versus task-induced values observed at study entry and greater than pre-/posttreatment changes seen in patients randomized to the WLC. A similar pattern emerged with respect to NKCA over the intervention period, which was independent of the changes in NK cells. There were no differences between patients assigned to EEGP and WLC in HR, DBP and SBP responses as well as in changes in PWM- and PHA-induced lymphocyte proliferation in response to the speech task measured before and after the 3-month intervention period. Individual differences in pre-/posttreatment increases in emotional expression but not in psychological distress were significantly associated with smaller changes in the number and function of NK cells over the 3-month period. CONCLUSIONS: These findings may indicate that emotional expression during EEGP may render breast cancer patients more comfortable expressing their emotional responses to the speech challenge, which, in turn, results in smaller stress-induced changes in NK cells and function.

An exploratory study into the effect of exhausting bicycle exercise on endocrine and immune responses in post-menopausal women: relationships between vigour and plasma cortisol concentrations and lymphocyte proliferation following exercise.

It is well-established that bicycle exercise alters the endocrine and immune responses in men, but little information is available for women, especially middle-aged, post-menopausal women. The purpose of our study was to document the endocrine and immune reactivity to exhausting bicycle exercise in post-menopausal women, and to explore whether complaints of fatigue or low vigour are related to these exercise-induced responses. Thirteen healthy post-menopausal women participated in this study. We used a graded exercise protocol to study the kinetics of activation of the endocrine and immune system. We chose to examine hormones related to the hypothalamus-pituitary-adrenal (HPA) system such as adrenocorticotropin hormone (ACTH) and cortisol and hormones related to the pituitary such as prolactin (PRL) and growth hormone (GH). With regard to the immune system, we examined the natural killer (NK) cell activity and pokeweed (PWM)-induced lymphocyte proliferation in addition to changes in peripheral blood cell counts. Our results demonstrate that acute physical stress results in a strong release of ACTH, cortisol, GH and PRL. The bicycle test significantly increased the number of CD3+, CD4+, CD16/56+ (NK cells) and CD8+ cells in our group of post-menopausal women. Interestingly, NK activity did not increase significantly despite an increase in NK cell numbers. PWM-induced lymphocyte proliferation did not change either. In addition, our data support the hypothesis that low vigour in post-menopausal women interferes with the endocrine and immune responses to exhausting exercise. In women with complaints of low vigour we found lower cortisol responses and higher increments in the proliferative capacity of lymphocytes as compared to those with high vigour scores. NK activity was unrelated to exhaustive mood states. These data indicate that endocrine as well as immune system activity changes in response to exhausting exercise in middle-aged, post-menopausal women. In addition, exhaustive mood states may contribute to cortisol responses and function of peripheral immune cells in post-menopausal women following exhausting exercise.

The effect of depressive symptomatology on plasma cortisol responses to acute bicycle exercise among post-menopausal women.

The present study was designed to elucidate the effect of depressive symptomatology on the cortisol response to strenuous exercise. Thirteen healthy, post-menopausal women participated in this study. The results show that acute bicycle exercise activates the hypothalamic-pituitary-adrenal (HPA) axis resulting in rapid increases in plasma cortisol. Concerning the effect of depressive symptomatology on cortisol release during physical performance, we found a trend toward a negative relation between the level of depression and the change in cortisol measured after termination of the exercise, but it failed to reach statistical significance, probably due to the small sample size. Interestingly, we found a significant negative correlation between basal cortisol levels and cortisol release to the exercise protocol. Although this finding is preliminary, it seems to suggest that a sustained activation of the HPA axis may coincide with an adrenal insufficiency in response to physical performance of post-menopausal women.

Altered immune function in human newborns after prenatal administration of betamethasone: enhanced natural killer cell activity and decreased T cell proliferation in cord blood.

During the course of human pregnancy, glucocorticoid (GC) treatment is given when preterm delivery is expected. This treatment is successful in stimulating the development of the fetal lung. However, in animal studies, a number of side effects of perinatal GC treatment have been described. The aim of the present study was to evaluate in humans the effects of antenatal GC treatment on development of the immune system. In addition, we examined the development of immune reactivity in infants born preterm and at term who did not receive GC treatment antenatally. We tested mitogen-induced T cell proliferation, natural killer cell activity, and lipopolysaccharide-induced IL-6 production in cord blood samples. We found that there is a significant effect of gestational age on the capacity of T cells to proliferate and of natural killer cells to kill K562 tumor cells. The capacity to produce IL-6 does not change between gestational age 26 and 41 wk. Moreover, our results show that antenatal treatment with GC does have immunomodulatory effects: T cell proliferation is decreased in infants born very preterm (gestational age 26-31 wk) as well as in infants born between 32 and 36 wk of gestation. In contrast, the activity of natural killer cells is only increased in GC-treated infants born between 26 and 31 wk. We did not observe a significant effect of antenatal GC treatment on the capacity to produce IL-6.

Effect of mild acute stress on immune cell distribution and natural killer cell activity in breast cancer patients.

The present study explored cardiovascular and immune responses to a standardized laboratory challenge (speech task) in 23 breast cancer patients. All patients were diagnosed with positive axilliary lymph nodes and received tamoxifen as an adjuvant treatment throughout the course of the study. As a control group, 15 age-matched healthy women were included. At baseline, there were no differences in blood pressure and heart rate values between breast cancer patients and healthy women. With respect to the lymphocyte subsets at baseline, patients had significantly higher absolute numbers of CD16/56 (NK) cells. We speculate that the increase in circulating NK cells can be either a sign of activation of aspecific natural immunity caused by tumor cells or an immunostimulatory effect of tamoxifen. No differences were found in total lymphocyte count and numbers of CD3, CD4, CD8 or CD19 (B) cells. The pattern of changes induced by the speech task with regard to number and function of peripheral immune cells confirm earlier findings derived from healthy subjects. Overall, marked increases were observed in NK and CD8 cells, whereas smaller changes were observed in number of CD4 and CD19 (B) cells in response to the speech task. There were no significant differences in the acute stress-induced immune cell changes between breast cancer patients and healthy women. These results seem to implicate that the distribution of immune cells is intact in patients with localized breast disease. With respect to natural killer cell activity (NKCA), our results, as do those of others, show a significant increase in response to the speech task in both healthy women and patients. Compared to the NKCA responses of healthy women, those of breast cancer patients appeared to be delayed. Potential mechanisms behind this difference are discussed.

Cardiovascular and immune responses to acute psychological stress in young and old women: a meta-analysis.

OBJECTIVE: To describe the relationships between cardiovascular and natural killer (NK) cell number changes on acute psychological stress in women. METHOD: Data from eight different studies were analyzed. A total of 128 healthy female subjects, 85 younger (18-45 years) and 43 older (49-87 years), had been subjected to a speech stressor (N = 80) or a mental effort stressor (N = 48), mental arithmetic, or the Stroop test. Correlations between changes in NK cell numbers, systolic (SBP) and diastolic (DBP) blood pressure, and heart rate (HR) were computed. Meta-analysis programs were used to study correlations across studies and to examine whether correlations differed with stressors or age. RESULTS: In all studies, significant increases over baseline were observed for each variable. Across studies, the mean weighted r between changes in HR, DBP, and SBP was medium (rw = .25) to large (rw = .64). A medium to large average correlation between HR and NK changes (rw = .37) was observed, whereas average correlations of changes in NK cell numbers with blood pressure changes were small to medium (rw < or = .23). Correlations between changes in NK cell numbers and cardiovascular variables were homogeneous across studies, whereas mutual correlations between cardiovascular variables were heterogeneous. One moderator variable showed itself: correlations between HR and DBP reactions were larger in studies with older than younger subjects. CONCLUSION: NK cell changes and HR responses induced by acute stress in women are regulated, to some extent, by the same mechanisms. Neither the type of stressor nor age seem to be very important when considering correlations between NK cell and cardiovascular changes. This study integrates information about NK cell and cardiovascular responses in women that can be used as reference material in future studies.

Effectiveness of a short-term group psychotherapy program on endocrine and immune function in breast cancer patients: an exploratory study.

Cancer patients who had been treated for early stage breast cancer and were diagnosed with either positive axillary lymph nodes or distant metastases were randomly assigned to either a 13-week experiential-existential group psychotherapy (EEGP) program or a waiting list control (WLC) condition. Endocrine and immune measures were obtained before and after the intervention period. The findings of this study are that, after the 13 weeks of the experiment, patients in the EEGP group showed lower levels of plasma cortisol and lower levels of prolactin as well as lower percentages of natural killer cells, CD8 cells, and CD4 cells in addition to a lower proliferative response to pokeweed mitogen than patients in the WLC group. Importantly, this was only found in those breast cancer patients presenting relatively high endocrine and immune baseline levels, suggesting that the patients' profile with regard to endocrine and immune function at the start of a program can have an important effect. If replicated on a larger scale, the current results may be relevant for the treatment of breast cancer.

Relations of plasma ACTH and cortisol levels with the distribution and function of peripheral blood cells in response to a behavioral challenge in breast cancer: an empirical exploration by means of statistical modeling.

This study explores by means of statistical modeling the relations between adrenocorticotrophin hormone (ACTH) and cortisol levels and distribution and function of peripheral blood cells in response to an acute stressor consisting of a standardized speech task in breast cancer patients with axillary lymph node metastases and distant metastases. As a control group age-matched women participated in this study. The preliminary findings show that the effect of ACTH on immunoreactivity is related to the health of the doctor. In node-positive breast cancer patients and healthy women, ACTH has a modest positive effect on T lymphocyte percentages and on pokeweed-induced proliferation at baseline and in response to the speech task. In contrast, in breast cancer patients with distant metastases, ACTH has a negative effect on T lymphocyte and function at baseline and in response to the stressor. Interestingly, neither ACTH nor cortisol levels were related to natural killer (NK) cell percentages and natural killer cell activity (NKCA). In addition, it appeared that cortisol had a positive effect on CD3 cell percentages when the health of the donor was taken into account. This effect was most distinct on CD3 cells measured at baseline. If replicated on a larger scale, these findings may indicate that the hypothalamic pituitary adrenal axis plays a role in the adaptation of the host defenses in reaction to acute stress, particularly those involving T lymphocytes. Moreover, these findings may suggest that the health of the donor may be an important effect modification factor in the relations between neuroendocrines and immunoreactivity.

Adjustment to breast cancer: the psychobiological effects of psychosocial interventions.

This review focuses on the effects of psychosocial interventions on psychological and biological functioning of breast cancer patients. Once in their lifetime, one out of eleven women receive a diagnosis of breast cancer. A diagnosis of breast cancer is a severe stressful life event with profound consequences on all aspects of human life. Whether a woman will regain emotional balance and accept the idea of living with a potentially life threatening disease depends on her psychological resiliency. Provision of psychosocial interventions can improve these women's coping abilities and reduce emotional distress and feelings of isolation, and improve psychosexual functioning. Additionally, there exists some evidence that psychotherapy may prolong survival. Prolongation of survival may be related, in part, to an increase in certain aspects of immune function (e.g., natural killer cell activity). This is plausible because the function of the immune system seems to be related to mammary tumor growth. Therefore, future research should examine the degree to which the effects on mammary tumor growth relate to immune system changes.

Elevated basal cortisol levels and attenuated ACTH and cortisol responses to a behavioral challenge in women with metastatic breast cancer.

Hormones of the hypothalamic-pituitary-adrenal system were studied in 31 patients with early stage breast cancer and patients with metastatic breast cancer. Both groups received tamoxifen as first-line treatment. As a control group 15 age-matched healthy women participated in the study. The results showed that breast cancer patients had significant elevations in basal cortisol levels compared to controls. Metastatic breast cancer patients had higher cortisol levels than early stage breast cancer patients. No significant differences between breast cancer patients and controls were found in basal plasma ACTH and prolactin levels. These data provide evidence that breast cancer is associated with a hyperactive adrenal gland, which may be due to the physiological stress associated with the presence of (micro)metastases or tumor cells in the circulation, in combination with administration of tamoxifen. In response to a behavioral challenge increases were observed in plasma ACTH and prolactin. Metastatic breast cancer patients had a faster prolactin response to acute stress than healthy women. However, metastatic breast cancer patients showed a blunted ACTH response compared to healthy women. Stress-induced ACTH responses and basal cortisol levels were negatively correlated in the metastatic group only. Thus, the blunted ACTH response to the behavioral challenge might be related to hypercortisolemia suggesting that the pituitary corticotroph cell in metastatic cancer is appropriately restrained possibly by the negative feedback effects of chronic cortisol elevations. Interestingly, the behavioral challenge induced decreases in cortisol levels in all three groups. However, metastatic breast cancer patients had a faster cortisol decline compared to healthy women. We hypothesize that this is caused by increased metabolic clearance of cortisol due to increased utilization of metabolic substrates often observed in the presence of a tumor.