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Endocrine Levels at the Start of Treatment Are Associated With Subsequent Psychological Adjustment in Cancer Patients With Metastatic Disease

From the Department of Behavioral Science (L.C., C.D., D.D.), The University of Texas M. D. Anderson Cancer Center, Houston, TX; Behavioral Medicine and Oncology (A.B.), University of Pittsburgh Cancer Institute, Pittsburgh, PA; and Department of Urology (R.J.A.), Baylor College of Medicine, Houston, TX.

Address reprint requests to: Lorenzo Cohen, PhD, Department of Behavioral Science, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 243, Houston, TX 77030. Email: lcohen{at}mdanderson.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION NOTES ACKNOWLEDGMENTS REFERENCES

 
OBJECTIVE: This study examined the association between hormonal profiles at the start of cancer treatment and subsequent psychological symptomatology.

METHODS: Twenty-seven patients with metastatic renal cell carcinoma and 18 patients with metastatic melanoma completed three assessments during the course of treatment: at the start of treatment (baseline), at the end of treatment (3 weeks after baseline), and at a follow-up appointment 1 month later. Cortisol, norepinephrine, and epinephrine levels were measured at baseline using 15-hour urine samples. At each assessment, patients completed the Impact of Event Scale (IES) and the Brief Symptom Inventory (BSI).

RESULTS: Patients reported moderate levels of distress throughout treatment as measured by the IES and BSI. Norepinephrine levels at the start of treatment were positively associated with IES total scores at the end of treatment and at follow-up, and cortisol levels were positively associated with IES total scores at follow-up after adjusting for baseline IES and overall distress scores. Norepinephrine levels were also positively associated with depression scores at follow-up, and cortisol levels were positively associated with depression scores at the end of treatment and at follow-up after adjusting for baseline depression and overall distress scores.

CONCLUSIONS: Hormonal profiles at the start of cancer treatment are associated with subsequent psychological adjustment.

Key Words: cortisol, • norepinephrine, • depression, • intrusive thoughts, • cancer.

Abbreviations: BSI = Brief Symptom Inventory;; GSI = Global Severity Index;; HPA = hypothalamic-pituitary-adrenal (axis);; IES = Impact of Event Scale;; MDD = major depressive disorder;; MVA = motor vehicle accident;; PTSD = posttraumatic stress disorder;; SNS = sympathetic nervous system.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION NOTES ACKNOWLEDGMENTS REFERENCES

 
The psychological difficulties experienced by individuals with cancer have been increasingly conceptualized within a trauma framework (1–3). Cancer patients often experience adjustment difficulties, including distress; fear of death, recurrence, or progression of disease; changes in quality of life and social relationships; and an overall loss of control (4, 5). In addition, the cancer experience is often associated with mood and anxiety disorders (3, 6). Estimates of the incidence of depression among cancer patients vary widely. For example, in their recent review of studies using various methods of assessment, Massie and Popkin (7) reported an incidence of depression among cancer patients of 6% to 42%. Research has also shown that cancer patients often have elevated levels of intrusive thoughts concerning their cancer and its treatment (8–11). Levels of intrusive thoughts are typically high at the time of diagnosis and may persist for months or even years after the initial diagnosis and treatment (12). Especially intense or prolonged intrusive thoughts seem to be associated with psychological distress (12, 13). Intrusive thoughts experienced by cancer patients have also been associated with posttraumatic stress disorder (PTSD), which may be elicited by a life-threatening illness (1–3, 8, 14). However, it is important to consider that intrusive thoughts often occur in the absence of PTSD and in concert with other disorders, including depression and anxiety.

Psycho-oncology research has focused on identifying and understanding the psychosocial factors that contribute to mood- and anxiety-related difficulties among patients with cancer (2, 3, 12). However, no research to date seems to have examined physiological factors that may be associated with various psychological symptoms in cancer patients. Research in patients with PTSD or major depressive disorder (MDD) has shown that there are distinct endocrine profiles associated with the two disorders (15–19). For example, MDD has been associated with hypercortisolism (18, 20–22). Affected patients show heightened levels of cortisol and a decreased sensitivity to the usual inhibition of the hypothalamic-pituitary-adrenal (HPA) axis, as shown by failure to suppress endogenous cortisol response secretion after dexamethasone challenge (20). Sympathetic nervous system (SNS) activity also tends to be heightened in patients with MDD; this increase in SNS activity is associated with increased circulating levels of norepinephrine and epinephrine (23). This hormonal profile is similar to that seen in individuals exposed to chronic stressors (17, 24). People who develop PTSD after a trauma tend to have low cortisol levels, increased sensitivity of the HPA axis (25), and increased levels of norepinephrine (19, 26) compared with people who do not develop PTSD. It has been difficult, however, to determine causality between the endocrine changes and the development of depressive disorders or PTSD because most of the research has been conducted in patients who have had the disorders for an extended time (27). However, findings from recent prospective research suggest that an individual’s hormonal profile immediately after a traumatic event may make them more vulnerable to subsequent development of significant adjustment difficulties (eg, MDD or PTSD) (28–30).

In the present exploratory study, we examined the association between endocrine function at the start of treatment and subsequent psychological adjustment in patients with metastatic renal cell carcinoma or metastatic melanoma who were participating in a phase I active immunotherapy trial of an autologous tumor preparation. Phase I clinical trials are the first step in evaluating the toxicity and potential efficacy of new antineoplastic agents in humans. In particular, phase I trials are typically designed to determine toxicity, the maximum tolerated dose, and the recommended dose for the phase II study, and often to examine the pharmacokinetics of the new agent. There is some chance that a patient may have a favorable response in a phase I trial, but often patients are treated at low and sometimes ineffective dosages (31). Phase I trials are conducted in patients with advanced disease, who often view the trial as their last hope for cure (32). However, fewer than 5% of patients generally respond to treatment (33–35), which adds to the stress of participating in these trials. The treatment patients received in this study, an autologous tumor vaccine, had no side effects; therefore, the treatment itself would not affect psychological adjustment. The goal of the clinical trial was not to determine the maximum tolerated dose but to examine the feasibility of the treatment, examine three different doses of treatment, and determine whether the treatment was associated with any systemic effects. We evaluated whether endocrine measures and symptoms of distress at the start of the trial were associated with psychological adjustment at the end of the trial and at follow-up. We hypothesized that psychological and physiological aspects of stress at the start of the trial would be positively associated with intrusive thoughts, avoidance behaviors, and symptoms of depression at the end of treatment and at follow-up.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION NOTES ACKNOWLEDGMENTS REFERENCES

 
Participants
Participants were patients with either metastatic renal cell carcinoma or metastatic melanoma who were enrolled in a phase I/b trial of a nontoxic, active, specific immunotherapy consisting of an autologous tumor preparation. Patients received injections once weekly for 4 weeks. All patients who were in the clinical trial were eligible for participation in the psychosocial trial. To be eligible for the clinical trial, patients had to have a life expectancy of greater than 4 months, a Zubrod performance status of 2 or less or a Karnofsky performance status exceeding 80%, and no serious intercurrent medical illness. None of the patients were taking any medication that could cause immune or hormone irregularities, and this was monitored across the trial by the clinic staff and a self-report questionnaire. All patients with renal cell carcinoma had newly diagnosed disease, all had stage IV disease, and none had received any chemotherapy or immunotherapy. The melanoma patients had either stage III or IV disease and had not received any medical treatment in the 4 weeks before the start of treatment. All renal cell carcinoma patients underwent a nephrectomy, and all melanoma patients underwent surgery to remove soft tissue or visceral sites of disease as part of routine melanoma management. The tumor specimens were used to prepare a tailored vaccine for each patient. At least 4 weeks after surgery, the patients began treatment with the autologous vaccine, which they received weekly for 4 weeks. Patients were then clinically evaluated 1 month after the end of treatment. There was no toxicity directly attributable to the vaccine treatment. Therefore, the possible side effects usually associated with phase I trials did not confound the relationship between the endocrine variables and psychological adjustment.

Procedure
After providing informed consent, patients completed a battery of questionnaires on the day of the first treatment (T1, baseline) and provided 15-hour urine samples for endocrine function analyses. They completed a second battery of questionnaires 3 weeks later (T2), on the day of the fourth and final treatment, and a third battery 1 month after the end of treatment during a routine follow-up visit (T3). At each assessment, patients completed measures of intrusive thoughts, avoidance behaviors, and symptoms of distress, as detailed below.

Measures
Questionnaires.
Intrusive thoughts, or the tendency to ruminate on or to avoid thoughts about stressors, were assessed using the Impact of Event Scale (IES) (36). The IES is a 15-item, self-report scale that assesses two categories of cognitive responses to stressful events: intrusion (intrusively experienced ideas, images, feelings, or bad dreams) and avoidance (consciously recognized avoidance of certain ideas, feelings, or situations). The scale was originally developed to assess current distress associated with a specific trauma. Patients in the present study were asked to rate the frequency of intrusive thoughts and avoidance behaviors in relation to their current health status. The internal reliabilities of each subscale were high at each time (intrusion: 0.86, 0.90, and 0.89; avoidance: 0.77, 0.83, and 0.85). The correlation between the intrusion and avoidance subscales at each time was high (T1: r = 0.76; T2: r = 0.77; T3: r = 0.78); therefore, the IES total score was used for the analyses.

Symptoms of depression and overall distress were measured with the Brief Symptom Inventory (BSI) (37). This widely used symptom inventory, a 53-item version of the Symptom Checklist 90–R (38), yields an overall distress score (Global Severity Index [GSI]) as well as subscale scores of depression, somatization, anxiety, phobic anxiety, hostility, obsessive-compulsive behavior, interpersonal sensitivity, paranoid ideation, and psychoticism. Patients were asked to rate the level of distress associated with each symptom they had experienced during the past week. In the current study, we were especially interested in the BSI depression scale and the GSI scores as a measure of depressive symptoms and overall distress. The internal reliabilities of the GSI and BSI depression scale at each time were high (GSI: 0.94, 0.97, and 0.92; BSI depression: 0.87, 0.88, and 0.85).

Background and medical measures.
Patients completed a background questionnaire that assessed age, employment status, marital status, education, and household income. In addition, medical information was abstracted from patient charts; this information included the number of metastatic sites, stage of disease, and date of initial diagnosis. The date of diagnosis with initial disease was used to calculate the length of time patients had known they had cancer at the time they completed the first assessment battery. Time since diagnosis, number of metastatic sites, and stage of disease were examined as possible covariates to control for severity of disease.

Endocrine variables.
The hormones measured were norepinephrine, epinephrine, and cortisol. All patients provided 15-hour urine samples, starting at 6 PM the night before the first treatment until 9 AM, when they were due to be at The University of Texas M. D. Anderson Cancer Center for their clinic appointment. Patients collected all urine in a plastic container containing 1 g of sodium metabisulfite (a nontoxic preservative), and they were asked to keep the samples on ice in coolers that were provided. The 15-hour collection period, rather than the standard 24-hour period, was used to decrease the burden on patients and to increase overall compliance. Importantly, the samples were collected across the same period of the circadian cycle. This 15-hour collection time has been used extensively in other studies examining stress and endocrine function and corresponds to periods of relatively low physical activity but possibly greater levels of rumination or thinking about upcoming stressors (24, 30, 39). On arrival at M. D. Anderson, a 12-ml aliquot was obtained (2 ml for cortisol and 10 ml for catecholamine measurements) and immediately frozen at -20°C until the time of assay. Patients also completed a checklist of foods that affect endocrine function; indicated whether they were smokers and if yes, how many cigarettes they had smoked in the past 24 hours; and listed any medications they were taking. Samples were shipped on dry ice to the Behavioral Medicine Endocrinology Laboratory at the University of Pittsburgh. Concentrations of free epinephrine and norepinephrine were measured in nanograms per milliliter using a competitive binding-site high-performance liquid chromatography, and cortisol levels were measured in nanograms per milliliter using radioimmunoassay. All samples were run in duplicate, and no two results differed by more than 10%. The values were calculated as the total nanograms per 15 hours (Concentration x Urine Volume), and in the analyses we controlled for total urine volume.

Statistical Analyses
Before testing the study hypotheses, we first examined variables that could be associated with either the dependent or independent variables. Several disease status variables were examined as possible covariates of psychological adjustment. However, there were no associations of the psychological variables at any time with age, number of metastases, stage of disease, time since diagnosis, time since surgery, or type of cancer. In addition, less than 10% of the patients smoked, and there was no association of caffeine intake, food items checked, or smoking status with the endocrine levels. There were also no associations of age, number of metastases, stage of disease, time since diagnosis, or time since surgery with the endocrine levels. However, patients with melanoma had significantly higher levels of norepinephrine (p < .01) and epinephrine (p < .007). Therefore, type of cancer was used as a covariate in all analyses examining the endocrine variables.

Pearson correlation analyses were performed to examine the association between IES total and BSI depression scores at baseline and IES total and BSI depression scores at the end of treatment and at follow-up. Separate hierarchical multiple regression analyses were performed to examine the association between each hormone level at baseline (norepinephrine, epinephrine, and cortisol) and the outcome measures (IES total and BSI depression scores) at the end of treatment and at follow-up. The covariates for the analyses included type of cancer, urine volume, the respective baseline level of the outcome measure (IES total or BSI depression score), and baseline levels of overall distress (GSI; the BSI depression scale was removed for the depression analyses) to control for psychological adjustment at the start of the trial. Model assumptions were evaluated using standard residual-based diagnostic procedures. A square-root transformation was performed for the BSI depression scores at each time because of a nonnormal distribution of the scores. No influential cases were identified.

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION NOTES ACKNOWLEDGMENTS REFERENCES

 
Of the 36 patients with metastatic renal cell carcinoma and 26 patients with metastatic melanoma recruited, 6 patients with melanoma and 2 patients with renal cell carcinoma did not comply with urine collection requirements at baseline, and 1 patient with melanoma did not complete the psychosocial measures at baseline. There were no statistically significant differences between the 53 respondents who had complete data at T1 and nonrespondents at T1 (N = 9) with respect to demographic or medical variables. In addition, two patients with renal cell carcinoma did not complete the T2 assessment, and five patients with renal cell carcinoma and one patient with melanoma did not complete the T3 assessment. Therefore, complete data were available for 45 patients. There were no statistically significant differences between the 45 participants who completed all the assessments and the 8 patients who completed the T1 assessment but did not complete the other assessments with respect to demographic and medical variables or baseline psychosocial characteristics. However, given the small number of patients with missing data, these tests have limited power. Patients who did not complete the T3 assessment but did complete the T2 assessment had significantly higher BSI depression scores at T2 than did patients who completed all assessments (Mann-Whitney U test, p < .02). These patients were feeling too sick at the time (N = 2), had already been taken off the trial because of advancing disease (N = 3), or had died (N = 2) before the T3 assessment. Table 1 lists the demographic and medical characteristics of the 45 patients for whom we had complete data. Ninety percent of the patients were non-Hispanic white. There were no differences between the two cancer groups in terms of the psychosocial outcome measures. The two cancer groups were therefore combined for all analyses.

Although we did not collect hormonal data in a healthy control group, we compared our results to those of Hawk et al. (39), who collected 15-hour urine samples (6 PM to 9 AM) in men and women 1 month after they had been in a motor vehicle accident (MVA) and from matched control subjects who were in the hospital 1 month earlier for a minor accident. The assays for both studies were conducted in the same laboratory. For comparison purposes, our values were converted to the rate of hourly excretion (ng/h) using the following formula: (Concentration x Urine Volume)/15. The cancer patients had higher cortisol and norepinephrine levels than the MVA and control subjects (cortisol: cancer, 3916 ± 2371; MVA, 2491 ± 2629; control, 1988 ± 1600; norepinephrine: cancer, 1445 ± 969; MVA, 1335 ± 1147; control, 936 ± 685). Interestingly, however, the epinephrine levels in the cancer patients were lower than those in the MVA and control subjects (epinephrine: cancer, 253 ± 113; MVA, 499 ± 305; control, 542 ± 340). This may explain why we did not find an association between epinephrine levels and any of the psychological adjustment measures.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION NOTES ACKNOWLEDGMENTS REFERENCES

 
Patients participating in the phase I cancer clinical trial of immunotherapy reported modest levels of intrusive thoughts, avoidance behaviors, and depressive symptoms throughout treatment and follow-up. Not surprisingly, high IES total scores and symptoms of depression at the start of the trial were associated with poorer psychological adjustment throughout the trial. The present study also revealed that norepinephrine levels at the start of treatment were positively associated with symptoms of depression at follow-up, and IES total scores at the end of treatment and at follow-up, after controlling for initial levels of distress and the respective outcome variable. Cortisol levels were positively associated with symptoms of depression at the end of treatment and at follow-up, and IES total scores at follow-up, after controlling for initial levels of distress and the respective outcome variable.

Although correlational, our findings are consistent with the hypothesis that hormone levels at the start of cancer treatment are associated with the subsequent frequency of intrusive thoughts, avoidance behaviors, and symptoms of depression, even after the initial level of psychological adjustment is taken into account. The association between norepinephrine levels and the IES total score is consistent with findings in the PTSD literature (19, 26, 28). Pitman (40, 41) suggested that the increased levels of norepinephrine and SNS activity could lead to an overconsolidation of the memories associated with the trauma, a process called "superconditioning," in turn leading to the hallmark symptoms of PTSD, an increased frequency of intrusive thoughts and avoidance behaviors. This hypothesis is supported by animal studies that have shown an association between norepinephrine levels and memory consolidation (42–44). Cortisol levels in the present study were positively associated with IES total scores at the follow-up assessment, which is inconsistent with findings of previous PTSD research (19, 30). Yehuda et al. (19, 28) suggest it may be the combination of increased norepinephrine and decreased cortisol levels that leads to the subsequent development of PTSD. However, the presence of intrusive thoughts and avoidance behaviors is just one of the criteria for PTSD, and the patients in our study were experiencing only moderate levels. The positive association between cortisol levels and IES total scores is consistent, however, with findings from research examining generalized symptoms of distress after trauma (24, 45). It is possible, therefore, that the symptoms exhibited by patients in our study reflect general distress rather than specific PTSD-like symptomatology.

The positive association between baseline cortisol and norepinephrine levels and symptoms of depression is consistent with findings from previous research conducted with patients diagnosed with MDD (17, 18, 21–23, 29). Although the patients in our study were not diagnosed with a depressive disorder per se, up to 18% of the sample were experiencing moderate to severe symptoms of depression (BSI depression scores of 0.66 or greater for men and 1.03 or greater for women) (37). This suggests that our patients were experiencing depressive symptoms and overall distress to a greater degree than they were experiencing symptoms of PTSD. However, as indicated, on average these patients were experiencing moderate levels of distress as measured by the GSI, and they reported lower levels than women with breast cancer at different phases of treatment (46) and survivors of advanced Hodgkin’s disease and acute leukemia (47). In comparison with the subjects who had experienced a MVA or the matched control subjects, the cancer patients had higher cortisol and norepinephrine levels. This suggests the cancer patients may have been experiencing increased HPA and SNS activity going into this phase I trial than MVA subjects 1 month after their accident. It is unclear why the cancer patients had lower epinephrine levels than the MVA and control participants. In the Hawk et al. (39) study, however, there were no differences in epinephrine levels 1 month after the accident between the MVA and control participants. In addition, we did not find an association between epinephrine levels and any of the psychological adjustment measures. Together this suggests that epinephrine may not be as good an index of stress responding as norepinephrine and cortisol.

Chrousos and Gold (17) suggest that a state of hyperarousal, or increased SNS and HPA activity, in and of itself may increase vulnerability to a depressive state and that dysregulation of the endocrine system will contribute to maintaining the individual in a depressed state. However, because of the dynamic nature of the system, it is difficult to determine cause and effect of such dysregulation. Hyperarousal may also interfere either directly or indirectly with appropriate cognitive integration of a traumatic experience (40), which has been found to influence adjustment (48, 49). Until such integration occurs, the traumatic event may be stored in active memory, leading to intrusive and emotionally disturbing thoughts. This may help explain why we did not find an association between endocrine function and psychological adjustment at the start of the trial, yet endocrine function at the start of the trial was associated with psychological adjustment over time. Hormonal profiles at the start of treatment may reflect patients’ anticipatory arousal before the start of the trial, which might diverge from their affective state assessed at the same time. Over time, however, the state of hyperarousal may interfere with the appropriate integration of the experience, leading to subsequent adjustment problems.

It is impossible to infer causality between hormone levels and psychological adjustment despite the association we observed. For example, the patients at baseline who were experiencing more intrusive thoughts were also experiencing more symptoms of depression, which might trigger HPA and SNS activation. However, the association between the hormone levels at the start of treatment and psychological adjustment at the end of treatment and at follow-up was significant even after controlling baseline levels of the respective psychological variables and for overall distress. This suggests that initial hormone levels independently contribute, at least in part, to subsequent psychological adjustment. Nonetheless, other factors that were not measured, such as sleep quality (which has been shown to be associated with depression and endocrine abnormalities), may have been influencing both variables (50). It is also important to note that although the percentage of the variance accounted for by urinary norepinephrine and cortisol levels was small (5–14%), the associations were robust considering we were predicting self-reported psychological adjustment at two separate time points from hormone levels collected 1 and 2 months earlier and that the effect remained even after removing the variance accounted for by baseline level of psychological adjustment.

A number of factors limit the generalizability of the current findings. We cannot exclude the possibility of preexisting conditions influencing the outcomes of this exploratory study because we were unable to obtain hormonal profiles or psychological measures before patients were diagnosed with their cancer and we did not assess previous psychiatric history. Because of this, it is difficult to differentiate whether our measures of psychological adjustment assessed a reactive state or a preexisting vulnerability to depression or other mood disorders. In addition, our measures of psychological adjustment are not as sensitive in making clinical diagnoses as are structured interviews. Having multiple assessments of hormonal functioning over several days would also have provided a more stable index of HPA and SNS activity. The generalizability of these findings to other cancer populations is limited because all of the patients had advanced disease and were participating in a phase I cancer clinical trial. Although provocative, these findings need to be replicated using a larger sample of cancer patients. Future research should prospectively examine psychological variables and endocrine function around the time of cancer diagnosis to better characterize the distress patients may be experiencing and the risk of developing adjustment problems. The use of structured interviews, determination of previous psychiatric history, and collection of 24-hour urine samples over several time points would improve some of the limitations of this study. The use of both psychological and biological indices of distress will help elucidate whether there is a psychobiological risk profile that predicts subsequent psychological morbidity.

The association between urinary hormone levels at the start of treatment and patients’ self-reported psychological adjustment 1 and 2 months later may be particularly relevant in light of recent findings. Sephton et al. (51) found that dysregulation of the diurnal salivary cortisol rhythms was associated with shorter survival time in women with metastatic breast cancer. In addition, Watson et al. (52) found that poor psychological adjustment (hopelessness/helplessness and depression) 4 to 12 weeks after diagnosis was associated with increased risk of relapse or shorter survival time in patients with breast cancer. Some research also suggests that the influence of psychosocial and endocrine factors on disease progression and overall survival is mediated by immune system mechanisms (53, 54). Although some research has found an association between psychosocial factors, endocrine function, and immune function, and these factors have been independently associated with survival (51, 52, 55, 56), a causal association between these three factors and disease progression and overall survival has not yet been established. Future research should extend the existing literature by directly examining the influence of endocrine function and psychological factors on immune system function and length of survival.

	ACKNOWLEDGMENTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION NOTES ACKNOWLEDGMENTS REFERENCES

 
This research was supported by a grant from the University Cancer Foundation, The University of Texas M. D. Anderson Cancer Center (L.C.). We thank Beatty Watts, Jawaria Gilani, Janet Sterner, and Zuneria Gilani for helping with data collection and Linda Murry and Mary Jo East for helping to coordinate the project. We thank Drs. Martica Hall and Douglas Delahanty for their insightful comments on this article. We thank Beth Notzon, from the Department of Scientific Publications, The University of Texas M. D. Anderson Cancer Center, for her helpful editorial comments on this article.

	NOTES

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION NOTES ACKNOWLEDGMENTS REFERENCES

 
Presented in part at the American Psychosomatic Society 59th Annual Scientific Meeting, Monterey, CA, March 6 to 10, 2001.

Received for publication November 13, 2000.

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