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Alpha-Amylase and Cortisol in Women with Endometrial Cancer

Permanent Link: http://ufdc.ufl.edu/UFE0041728/00001

Material Information

Title: Alpha-Amylase and Cortisol in Women with Endometrial Cancer Comparing Diurnal Profiles in Relation to Stress
Physical Description: 1 online resource (44 p.)
Language: english
Creator: Garey, Stephanie
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2010

Subjects

Subjects / Keywords: alpha, cancer, cortisol, psychoneuroendocrinology, stress
Clinical and Health Psychology -- Dissertations, Academic -- UF
Genre: Psychology thesis, M.S.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Alpha-amylase and cortisol are stress hormones produced via independent stress systems. Following stress, alpha-amylase is released by the sympathetic nervous system (SNS), while cortisol is released by the hypothalamic-pituitary-adrenal (HPA) axis. Although the psychoneuroimmunologic (PNI) mechanisms involved in HPA stress responses have been studied in medical populations, less is known about mechanisms of limbic HPA-independent alpha-amylase, particularly in cancer. This study (1) compared salivary alpha-amylase and cortisol levels, and (2) examined stress/anxiety and alpha-amylase relations among women scheduled for surgery for endometrial cancer. Participants included 15 women drawn from a larger study of PNI relations in endometrial cancer. Stress was measured with the Perceived Stress Scale and stress ratings (0 no stress to 10 highest stress possible) obtained at the time of saliva collection. Anxiety was measured using the Millon Behavioral Medicine Diagnostic and the Structured Interview Guide for the Hamilton Anxiety/Depression Scales. Saliva was collected at 8 AM, 12 PM, 5 PM, and 9 PM the day prior to surgery and assayed using ELISA. A moderate effect size correlation (r = -.34) emerged between greater 8 AM cortisol and lower 8 AM alpha-amylase. A moderate effect size correlation (r = .39) also emerged between greater changes in cortisol and greater changes in alpha-amylase per unit time. Furthermore, a large and statistically significant effect size correlation (r = .58) was revealed between greater 8 AM stress levels and greater 12 PM alpha-amylase. Statistically significant correlations emerged between greater anxiety and less change in alpha-amylase per unit time (r = -.72, p < .05) and less total diurnal output (r = -.71, p < .05), a possible pattern of SNS activity blunting. Although based on a small sample, these findings suggest stress/anxiety may be associated with SNS-dependent alpha-amylase in women with cancer. Future research should replicate and expand upon these findings in a larger sample.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Stephanie Garey.
Thesis: Thesis (M.S.)--University of Florida, 2010.
Local: Adviser: Pereira, Deidre B.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2010
System ID: UFE0041728:00001

Permanent Link: http://ufdc.ufl.edu/UFE0041728/00001

Material Information

Title: Alpha-Amylase and Cortisol in Women with Endometrial Cancer Comparing Diurnal Profiles in Relation to Stress
Physical Description: 1 online resource (44 p.)
Language: english
Creator: Garey, Stephanie
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2010

Subjects

Subjects / Keywords: alpha, cancer, cortisol, psychoneuroendocrinology, stress
Clinical and Health Psychology -- Dissertations, Academic -- UF
Genre: Psychology thesis, M.S.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Alpha-amylase and cortisol are stress hormones produced via independent stress systems. Following stress, alpha-amylase is released by the sympathetic nervous system (SNS), while cortisol is released by the hypothalamic-pituitary-adrenal (HPA) axis. Although the psychoneuroimmunologic (PNI) mechanisms involved in HPA stress responses have been studied in medical populations, less is known about mechanisms of limbic HPA-independent alpha-amylase, particularly in cancer. This study (1) compared salivary alpha-amylase and cortisol levels, and (2) examined stress/anxiety and alpha-amylase relations among women scheduled for surgery for endometrial cancer. Participants included 15 women drawn from a larger study of PNI relations in endometrial cancer. Stress was measured with the Perceived Stress Scale and stress ratings (0 no stress to 10 highest stress possible) obtained at the time of saliva collection. Anxiety was measured using the Millon Behavioral Medicine Diagnostic and the Structured Interview Guide for the Hamilton Anxiety/Depression Scales. Saliva was collected at 8 AM, 12 PM, 5 PM, and 9 PM the day prior to surgery and assayed using ELISA. A moderate effect size correlation (r = -.34) emerged between greater 8 AM cortisol and lower 8 AM alpha-amylase. A moderate effect size correlation (r = .39) also emerged between greater changes in cortisol and greater changes in alpha-amylase per unit time. Furthermore, a large and statistically significant effect size correlation (r = .58) was revealed between greater 8 AM stress levels and greater 12 PM alpha-amylase. Statistically significant correlations emerged between greater anxiety and less change in alpha-amylase per unit time (r = -.72, p < .05) and less total diurnal output (r = -.71, p < .05), a possible pattern of SNS activity blunting. Although based on a small sample, these findings suggest stress/anxiety may be associated with SNS-dependent alpha-amylase in women with cancer. Future research should replicate and expand upon these findings in a larger sample.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Stephanie Garey.
Thesis: Thesis (M.S.)--University of Florida, 2010.
Local: Adviser: Pereira, Deidre B.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2010
System ID: UFE0041728:00001


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1 ALPHAAMYLASE AND CORTISOL IN WOMEN WITH ENDOMETRIAL CANCER: COMPARING DIURNAL PROFILES IN RELATION TO STRESS By STEPHANIE LYNN GAREY A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE UNIVERSITY OF FLORIDA 2010

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2 2010 Stephanie Lynn Garey

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3 To my mother and father

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4 ACKNOWLEDGMENTS First and foremost, I thank Dr. Deidre Pereira for her continued mentorship and guidance throughout the course of this project. I also extend my appreciation to Timothy Sannes, Megan Lipe, Seema Patidar, and Rebecca Athanason for their guidance throughout this process. I acknowledge my committee, Dr. Russell Bauer, Dr. Stephen Boggs, and Dr. Glenn Ashkanazi. I would like to thank my family, friends, and classmates for their continued support during my time in graduate school. I extend my sincere thanks to t he women who participated in this research. Without them, this project would not have been possible.

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS .................................................................................................. 4 LIST OF TABLES ............................................................................................................ 7 LIST OF FIGURES .......................................................................................................... 8 ABSTRACT ..................................................................................................................... 9 CHAPTER 1 INTRODUCTION .................................................................................................... 11 Epidemiology of Endometrial Cancer ...................................................................... 11 Biobehavioral Factors Involved in Tumor Biology ................................................... 11 Mechanisms for Regulation of the Endocrine System ............................................ 12 Impact of Stress on Endocrine Functioning, Immunity, and Cancer ....................... 12 Biobehavioral Mechanisms of AlphaAmylase Production ...................................... 13 B iobehavioral Mechanisms of Cortisol Production .................................................. 14 Comparing AlphaAmylase and Cortisol Stress Profiles ......................................... 14 Psychosocial and Endocrine Relationships ............................................................ 15 Current Study .......................................................................................................... 16 2 METHODS .............................................................................................................. 18 Design ..................................................................................................................... 18 Participants ............................................................................................................. 18 Procedures ............................................................................................................. 18 Psychosocial Assessment ...................................................................................... 19 Anxiety .............................................................................................................. 19 Perceived Stress .............................................................................................. 20 Physiological Assessment ...................................................................................... 21 Saliva Collection and Storage .......................................................................... 21 Quantitation of Salivary Cortisol ....................................................................... 22 Quantitation of Salivary AlphaAm ylase ........................................................... 22 Operationalization of Cortisol and AlphaAmylase ........................................... 22 Statistical Analyses ................................................................................................. 23 Analyses of Specific Aims ................................................................................ 24 Analysis of Exploratory Aims ............................................................................ 24 3 RESULTS ............................................................................................................... 26 Preliminary Analyses .............................................................................................. 26 Normality Assumptions ..................................................................................... 26 Comparison to the Parent Study Sample ......................................................... 27

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6 Analyses of Specific Aims ....................................................................................... 28 Specific Aim 1: Comparison of AlphaAmylase and Cortisol 8 AM Values/Slopes ............................................................................................... 28 Specific Aim 2: Stress, Anxiety, and AlphaAmylase/Cortisol Slopes .............. 28 Exploratory Aim 3: Stress, Anxiety, and Other Markers of AlphaAmylase/Cortisol Levels ................................................................................ 30 4 DISCUSSION ......................................................................................................... 36 Study Limitations .................................................................................................... 37 Future Directions .................................................................................................... 38 LIST OF REFERENCES ............................................................................................... 40 BIOGRAPHICAL SKETCH ............................................................................................ 44

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7 LIST OF TABLES Table page 3 1 Histology distribution .......................................................................................... 32 3 2 Racial distribution ............................................................................................... 32 3 3 Regression o f cortisol and alphaamylase (sAA) levels on time of collection .... 32 3 4 Correlations between waking levels/diurnal slopes of cortisol and sAA ............. 32 3 5 Correlations between cortisol/sAA slopes and perceived stress/anxiety scores ................................................................................................................. 33 3 6 Correlations between waking levels/total diurnal output of cortisol and sAA, perceived stress, and anxiety ............................................................................. 33 3 7 Correlations between stress ratings at the time of collection and corresponding cortisol/sAA levels ....................................................................... 33

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8 LIST O F FIGURES Figure page 3 1 Mean alphaamylase and cortisol slopes ( n = 15) .............................................. 34 3 2 sAA and cortisol slopes for high anxiety versus low anxiety participants ............ 35

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9 Abstract of Thesis Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Master of Science ALPHAAMYLASE AND CORTISOL IN WOMEN WITH ENDOMETRIAL CANCER: COMPARING DIURNAL PROFILES IN RELATION TO STRESS By Stephanie Lynn Garey May 2010 Chair: Deidre B. Pereira Major: Psychology Alphaamylase and cortisol are stress hormones produced v ia independent stress systems. Following stress, alphaamylase is released by the sympathetic nervous system (SNS), while cortisol is released by the hypothalamic pituitary adrenal (HPA) axis. Although the psychoneuroimmunologic (PNI) mechanisms involved in HPA stress responses have been studied in medical populations less is known about mechanisms of limbic HPA independent alphaamylase particularly in cancer This study (1) compared salivary alphaamylase and cortisol levels, and (2) examined stress/anxiety and alphaamylase relations among women scheduled for sur gery for endometrial cancer. Participants included 15 women drawn from a larger study of PNI relations in endometrial cancer Stress was measured with the Perceived Stress Scale and stress ratings (0 [ no stress] to 10 [ highest stress possible]) obtained at the time of saliva collection. Anxiety was measured using the Millon Behavioral Medicine Diagnostic and the Structured Interview Guide for the Hamilton Anxiety/Depression Scales. Saliva was collected at 8 AM, 12 PM, 5 PM, and 9 PM the day prior to su rgery and assayed using ELISA.

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10 A moderate effect size correlation ( r = .34) emerged between greater 8 AM cortisol and lower 8 AM alphaamylase. A moderate effect size correlation ( r = .3 9 ) also emerged between greater changes in cortisol and greater changes in alphaamylase per unit time. Furthermore, a large and statistically significant effect size correlation ( r = .58) was revealed between greater 8 A M stress levels and greater 12 P M alphaamylase. Statistically significant correlatio ns emerged between greater anxiety and less change in alphaamylase per unit time ( r = .72, p <.05) and less total diurnal output ( r = .71, p <.05) a possible pattern of SNS activity blunting. Although based on a small sample, these findings suggest stres s/anxiety may be associated with SNS dependent alphaamylase in women with cancer. F uture research should replicate and expand upon these findings in a larger sample.

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11 CHAPTER 1 INTRODUCTION Epidemiology of Endometrial Cancer Endometrial cancer is a type of uterine cancer affecting the lining of the uterus, called the endometrium. It is the most common gynecologic cancer and the fourth most common type of cancer affecting women in the United States. In 2008, the estimated number of new endometrial cancer cases was 40,100, with an estimated number of deaths from endometrial cancer reaching 7,470. The American Cancer Society predicts that in 2009, the number of new cases will increase to 42,160, with an expected 7,780 deaths. In 2006, approximately 572,603 women in the United States had a history of endometrial cancer (National Cancer Institute, 2009). Mor t ality related to endometrial cancer is highest in African Americans, with 7.2 per 100,000 deaths compared to 3.9 per 100,000 deaths in Caucasians. The fiveyear survival rate for women diagnosed with endometrial cancer is 88%; however, the fiveyear survival rate for women who are diagnosed early in t he disease process increases to approximately 95% (American Cancer Society, 2008). Endometrioid adenocarcinoma, the most common type of endometrial cancer, has well established risk factors, including obesity, early onset of menses and/or late menopause, diabetes, and never having given birth. However, l ittle research has focused on how biobehavioral factors (i.e., psychological, behavioral, and physiological factors, in concert) may influence the progression of endometrial cancer. Biobehavioral Factors Involved in Tumor Biology Several studies have provided evidence for the influence of stress and other psychological factors on cancer progression (Antoni, Lutgendorf, Cole, Dhabhar, Sephton, McDonald, Stefanek, & Sood, 2006). Central nervous system activat ed

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12 responses to stress are initiated by both environmental and psychosocial processes. These stress responses follow two pathways: the autonomic nervous system ( ANS; fight or flight) and the hypothalamic pituitary adrenal axis (HPA; defeat/withdrawal). The se parallel stress systems both release hormones (i.e., gluco corticoids and catecholamines) in response to stress that can subsequently impact immune functioning due to dysregulation of the feedback system. Mechanisms for Regulation of the Endocrine System The endocrine system is regulated by the HPA, which releases hormones in response to stress. Through the initiation of a feedback loop, the hypothalamus is stimulated by the neurotransmitter gammaaminobenzoic acid (GABA). As a result, the hypothalamus se cretes corticotrophin releasing hormone (CRH), which stimulates the pituitary gland to release adrenocorticotropic hormone (ACTH). Finally, glucocorticoids including cortisol are released by the stimulation of the adrenal cortex by ACTH. Homeostasis is mai ntained because circulating cortisol levels determine whether further stimulation of the hypothalamus and release of CRH and ACTH is required (Kaye & Lightman, 2005). For example, low cortisol levels will prevent the suppression of CRH and ACTH release, while higher levels of circulating cortisol will reduce the amount of CRH and ACTH that is produced. However, under conditions of chronic stress and sustained circulation of glucocorticoids, this negative feedback system may cease to function, resulting in continued HPA activation and secretion of glucocorticoids ( Antoni et al., 2006). Impact of Stress on Endocrine Functioning, Immunity, and Cancer Endocrine factors can have a significant impact on immune function, particularly in response to the presence of stress. Stress modulates, or alters, immunity through

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13 increases in HPA and SNS activity, particularly affecting suppression of anti tumor immunity (Sephton & Spiegel, 2003) Although HPA and SNS activation in response to acute stress is adaptive, HPA and SNS activation in response to chronic stress is maladaptive, such that it decreases cell mediated i mmunity through suppressed synthesis of proinflammatory cytokines ( Antoni, Lutgendorf, Cole, Dhabhar, Sephton, McDonald, Stefanek & Sood, 2006; Thaker, L utgendorf, & Sood, 2007) A decrease in cellmediated immunity makes it harder for individuals to fight off infection. There is some evidence that cortisol may enhance this higher vulnerability to infection by SNS induced immunity implicated in cancer cell growth (Nakane, Szentendrei, Stern, Virmani, Seely, & Kunos, 1990), but less is known regarding the impact of alphaamylase on immunity. Biobehavioral Mechanisms of Alpha Amylase Production Salivary alphaamylase is an enzyme secreted in to the oral mucosa by the salivary glands and released by activation of the sympathetic nervous system (SNS) in response to stress (Granger, Kivlighan, El Sheikh, Gordis & Stroud, 2007). Although it can be measured in multiple bodily fluid compartments, it is often measured in saliva as it is the least invasive collection method. Primarily, alphaamylase functions biologically to aid in digestion. However, it plays a secondary role in the prevention and clearance of bacteria from the mouth which highlights its role in faci litating immunocompetence through the promotion of wound healing via inflammatory processes. Among healthy, nonstressed individuals, alphaamylase can be found in relatively high concentrations in the salivary glands where it peaks quickly and declines rapidly upon awakening. Diurnally, alphaamylase increases throughout the day following the initial rapid decline. Much like cortisol, acute physiological and

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14 psychological stress can cause levels of alphaamylase to rise. Several studies have shown that alpha amylase baseline concentrations and stress related changes are highly correlated with patterns of plasma norepinephrine release, suggesting adrenergic regulation of the stress system (Granger, Kivlighan, Blair, El Sheikh, Mize, Lisonbee, Buckhalt, Str oud, Handwerger, & Schwartz, 2006; Granger et al., 2007; Nater & Rohleder, 2009). Biobehavioral Mechanisms of Cortisol Production Cortisol is a stress hormone, specifically a glucocorticoid It is produced by the adrenal cortex and it is released by activation of the HPA axis. Under normal conditions, cortisol follows a typical diurnal pattern that is characterized by increased levels in the morning and decreased levels in the evening. During acute stress, cortisol levels rise and stay high throughout the course of the day, which is illustrated by a flattened slope. However, under conditions of chronic stress, the HPA system may become fatigued, resulting in a blunting of the diurnal cortisol rhythm. Comparing Alpha Amylase and Cortisol Stress Profiles Some studies have shown that cortisol has a similar diurnal profile to alphaamylase in healthy individuals (Granger et al., 2007); however, other studies have presented conflicting evidence, suggesting that alphaamylase has a large initial decline upon awakening followed by steadily increasing levels across the day. While mechanisms involved in the HPA stress response associated with chronic illness have been studied extensively (Kumar, Kumar Waldrop, Antoni, S ch neiderman & Eisdorfer, 2002; Reiche, Nunes, & Morimoto, 2004; Spiegel, Giese Davis, Taylor & Kraemer, 2006), the study of limbic HPA independent alphaamylase profiles in medical populations has not received much attention. The majori ty of studies indicate that

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15 individuals with chronic stress show increased cortisol and alphaamylase levels (Granger et al., 2007; Nater, Rohleder, Schlotz, Ehlert, & Kirschbaum, 2007; Van Veen, Van Vliet, DeRijk, Van Pelt, Mertens, & Zitman, 2008). Obtai ning knowledge regarding stress related changes in physiological processes both within and outside the HPA axis is critical to a comprehensive view of the stress response system. This information will be particularly useful in medically ill populations (i. e., cancer) who experience chronic stress secondary to diagnosis and treatment. Psychosocial and Endocrine Relationships There is a robust body of literature linking psychosocial factors to cortisol in cancer populations. Previous research has demonstrated connections between cortisol and several psychosocial factors in cancer patients, including depression (Jehn, Kuehnhardt, Bartholomae, Pfeiffer, Krebs, Regierer, Schmid, Possinger, & Flath, 2006; Reiche, Morimoto, & Nunes, 2005; Spiegel & Giese Davis, 20 03), anxiety (Miller, Ancoli Israel, Bower, Capuron & Irwin, 2008; Vedhara et al., 2003), PTSD (Cohen, Moor, Devine, Baum, & Amato, 2001), social support (Turner Cobb, Sephton, Koopman, Blake Mortimer, & Spiegel, 2000), sleep difficulties and fatigue (Bow er, Ganz, Dickerson, Petersen, Aziz, & Fahey, 2005; Bower, Ganz, & Aziz, 2005; Sephton, Sapolsky, Kraemer, & Spiegel, 2000), and benefit finding (Cruess, Antoni, McGregor, Kilbourn, Boyers, Alferi, Carver, & Kumar, 2000). For instance, i n one study of canc er patients, depression was associated with higher cortisol concentrations at 8 AM and 8 PM and dysfunctional cortisol variations ( Jehn et al., 2006). Another study of stress, depression, and anxiety in breast cancer patients revealed no correlations between psychological distress and levels of cortisol taken at specific time points across the day but associations were found between psychological distress (particularly stress and

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16 anxiety) and nonlinear rate of decline in cortisol (Vedhara, Miles, Bennett, Plummer, Tallon, Brooks, Gale, Munnoch, Schreiber Kounin, Fowler, Lightman, Sammon, Rayter, & Farndon, 2003). Despite this wealth of literature, little is known about relationships between cortisol and psychosocial factors in endometrial cancer, the 4th most common cancer among women. T here is also a significant gap in the literature about how psychological factors may be associated with alphaamylase in both healthy and disease populations Only one published study, to our knowledge, has assessed the relationship between alphaamylase and psychological factor s ( vanVeen et al. 2008). In this study, s alivary alphaamylase and cortisol were measured in a sample of adults diagnosed with social anxiety disorder (also known as social phobia) and were compar ed to a sample of healthy adults in a nonstressed condition and following a low dose of dexamethasone, a synthetic glucocorticoid hormone that suppresses HPA functioning Results indicated that diurnal alphaamylase profiles for individuals with social anxiety disorder were significantly different from cortisol profiles for both conditions, such that diurnal alphaamylase and alphaamylase levels post dexamethasone were found to be higher than cortisol levels. No significant differences were found between individuals with social anxiety disorder and healthy controls. Additionally, there is little known regarding potential relationships between psychosocial factors and alphaamylase, particularly in chronic, lifelimiting illnesses, including cancer. Curren t Study The current study intends to address these gaps in the literature by exploring the following specific aims:

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17 Specific Aim 1 : T o examine the relationship between waking levels/diurnal slopes of cortisol and alphaamylase in women with endometrial cancer Hypothesis 1a: At least a moderate negative effect size correlation will emerge between levels of alpha amylase at 8 AM and levels of cortisol at 8 AM Hypothesis 1b : Alpha amylase diurnal slope will reflect an overall increase in values across the day, while cortisol diurnal slope will reflect an overall decrease in values across the day (i.e., alphaamylase will h av e a more positive diurnal slope than cortisol ) Specific Aim 2 : To exam ine the association between perceived stress/anxiety and alphaamylase/cortisol slope in women with endometrial cancer. Hypothesis 2a: A t least a moderate effect size correlation will emerge between greater perceived stress and (i) less decrease in cortis ol per unit time, and ( ii) greater increase in alpha amylase per unit time (i.e., patterns suggestive of a blunted cortisol response and an exaggerated alphaamylase response, respectively ) Hypothesis 2b : At least a moderate effect size correlation will emerge between greater anxiety and (i) less decrease in cortisol per unit time, and (ii) greater increase in alphaamylase per unit time (i.e., patterns suggestive of a blunted cortisol response and an exaggerated alphaamylase response, respectively). Exp loratory Aim 3 : To explore relationships between stress /anxiety and additional markers of alphaamylase/cortisol levels (values at 8 AM, 12 PM, 5 PM, and 9 PM; and total diurnal output) in women with endometrial cancer. Hypothesis 3 : Given the exploratory nature of this aim, no specific hypotheses are offered.

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18 CHAPTER 2 METHODS Design The current study utilized a nonexperimental, crosssectional design. Briefly, participants provided psychosocial data immediately prior to surgery for suspected endometrial cancer. Furthermore, they collected saliva samples four times a day for three consecutive days prior to surgery (see Procedures below for additional detail). Participants Participants for this study were 1 5 women drawn from a larger, parent study jointly funded by the American Cancer Society and the National Cancer Institute (PI: Deidre Pereira, Ph.D. R03). Inclusion criteria for the parent study we re: (a) women with suspected primary endometrial cancer who were 18 or older, (b) undergoing a total abdominal hysterectomy with bilateral salpingo oophorectomy (TAH BSO), and (c) fluent in spoken English. Exclusion criteria were: (a) a diagnosis of recurr ent endometrial cancer, (b) metastasis from another site, (c) undergoing preoperative chemotherapy or radiotherapy, and (d) a current psychotic disorder or suicidal intent. Women were selected for this substudy if they had complete physiological (i.e., assayed cortisol and alphaamylase samples) and psychosocial data. Procedures Participants for this study were recruited from the Gynecologic Oncology Clinic at the University of Florida. Women who were potentially eligible for participation were identifie d during their preoperative consultation visits with a team of physicians residents, and nurses. If the patient expressed interest in study participation to the medical staff, she then met with a trained member of the research team to discuss study

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19 proce dures and address subsequent questions and concerns. Following confirmation that the patient was interested in participating, the patient read and signed an IRB approved Informed Consent Form. Upon providing consent and enroll ing in the study the participant underwent a brief psychiatric screening assessment. If the screening measure indicated a lack of psychiatric disturbance, the participant was then scheduled for a psychosocial interview during their preoperative visit to the Gynecologic Oncology Clinic. Participants were given questionnaires to complete and were instructed to collect saliva samples for the three days prior to their return appointment. At this appointment, participants underwent a psychosocial interview in one of the clinic rooms and returned their completed materials. Upon completion of the psychosocial interview and collection of materials, participants received $20 compensation to reimburse parking and transportation expenses. Psychosocial Assessment Anxiety Two instruments were used to assess anxiety. The Structured Interview Guide for the Hamilton Anxiety/Depression Scales (SIGH AD ) ( Williams, 1988) w as used to assess symptoms of anxiety over the past week. This measure is a semi structured interview based on the Hamilton Anxiety S cale (Hamilton, 1959) and the Hamilton Depression Scale (Hamilton, 1960) and has been used in the past with medical populations (Brown, Rundell, McManis, Kendall, Zachary, & Temoshok, 1992). In order to reduce patient burden and to exclude items that may also be associated with endometrial cancer symptomatology, t he present study used an abbreviated version that consisted of 15 items assessing depression and 9 items assessing anxiety Scores for the anxiety subscale ranged from 0 (no anxious symptoms) to 29 (severe anxious

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20 symptoms). This abbreviated version of the SIGH AD demonstrated good concurrent validity. SIGHAD depression scores (with and without organic ratings) were significantly correlated with Beck Depression Inventory second edition (BD I II; Beck, Steer, & Brown, 1996), r = .477, p < .05 and r = .623, p < .001 respectively. Additionally, SIGH AD anxiety scores were significantly correlated with Affects Balance Scale (ABS ; Derogatis, 1975) scores, r = .624, p < .001. The Millon Behavioral Medicine Diagnostic (MBMD) Anxiety Tension subscale was used to measure symptoms of anxiety that may interfere with medical care The MBMD is a 165item self report inventory that measures several psychological facets that can affect treatment progress and outcomes in patients with medical illnesses (Millon, Antoni, Millon, Minor & Grossman, 2001). The measure includes 29 subscales in addition to Response Pattern scales (i.e., disclosure, desirability, and debasement), a Validity indicator, and Negative Health Habits indicators (i.e., alcohol, drug, eating, caffeine, inactivity, and smoking). The Anxiety Tension subscale is considered a psychiatric indicator and elevations suggest that additional assessment of anxious symptomatology should be evaluated to d etermine an appropriate DSM IV diagnosis. The MBMD was normed on a medical population and demonstrated adequate reliability (internal reliability = .79; internal consistency = .83) in medical populations (Cruess, Minor, Antoni, & Millon, 2007). Perceived S tress Perceived stress was assessed in two ways. First, participants completed the Perceived Stress Scale (PSS) (Cohen, Kamarck, & Mermelstein, 1983) a 14item self report scale used to measure an individuals appraisal (perceptions) of situations as str essful during the week prior to surgical evaluation Participants rated the frequency

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21 of these 14 feelings, cognitions, and situations on a 5point scale (0 = never; 4 = very often). Examples of items included: In the last week, how often have you felt nervous and stressed? and In the last week, how often have you felt that you were unable to control the important things in your life? Several items were reverse scored so that higher ratings corresponded to greater perceived stress. Ratings were th en summed to yield a total perceived stress score with h igher scores indicat ing greater perceptions of stress. Second, participants provided stress ratings at the time of each saliva collection across the three days prior to surgery. Specifically, p articipants rated their stress levels on a scale of 0 (no stress) to 10 (highest stress possible). Physiological Assessment Saliva Collection and Storage Saliva samples were collected at 8 AM, 12 PM, 5 PM, and 9 PM for 3 consecutive days prior to partici pants preoperative visit in the Gynecologic Oncology Clinic. Participants were instructed to collect saliva samples using a Salivette (Starstedt, Inc., Newton, N.C.), which is a cylindrical plastic tube containing a cotton roll. Participants were instruc ted to place the cotton roll in their mouth and allow it to saturate with saliva for approximately 12 minutes. Additionally, participants were asked not to smoke, eat, drink liquids, or brush their teeth for the 30 minutes prior to collection. P articipant s were also instructed to write the exact time of collection and their stress ratings (0 10) on the plastic tube. Finally, participants were instructed to refrigerate the samples until they returned to the Gynecologic Oncology Clinic for their preoperative visit. Once the samples were returned to the researchers, they were stored in a freezer maintained at 80 degrees Celsius. Batches of samples were then shipped to

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22 Salimetrics, Inc. (State College, PA) where they were assayed. Only day 3 saliva collec tion will be used in the current study. Quantitation of Salivary Cortisol Salivary cortisol concentrations were obtained using an EnzymeLinked Immunosorbent Assay (ELISA) kit (Salimetrics, Inc., State College, PA). This method of kinetic measurement is c ommonly used in laboratory settings and involves combining an unknown amount of antigen with an antibody that is linked to an enzyme so that they may bind. Final ly, a substance is added to aid in the enzymes conversion resulting in the formation of variou s complexes that can be seen via the magnitude of fluorescence that they emit. This magnitude is read by a standard plate reader, which detects the optical density and determines cortisol levels based on the intensity of the color following binding with the substrate (tetramethylbenzidine). Quantitation of Salivary Alpha Amylase Salivary a lphaamylase concentrations were also obtained using an ELISA kit (Salimetrics, Inc., State College, PA), which is based on the same principles of measurement present in cortisol. The main differences lie in the type of substrate used (2 chlorop nitr o phenol) in the enzymatic reaction with alphaamylase and the amount of nanometers (405) required to measure optical density. Operationalization of Cortisol and Alpha Amylase Cortisol and alphaamylase levels were examined in several ways. First, morning (i.e., awakening) values were assessed by examining cortisol/alphaamylase concentrations at 8 AM on Day 3 of collection. Morning values reflect the bodys ability to respond physiologically to the stress of transitioning from sleep to wakefulness. Determination of abnormal 8 AM values is challenging. In psychoneuroendocrinology

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23 r e search, individual participants 8 AM values of cortisol and alphaamylase are generally compared to those of other participants in the overall sample. 8 AM values that are either g reatly elevated or much lower than other participants 8 AM values may be viewed as abnormal suggesting either an exaggerated or blunted response to waking Second, cortisol/alphaamylase slopes on Day 3 of collection were generated by regressing cortisol/alphaamylase concentrations at 8 AM, 12 PM, 5 PM, and 9 P M on time of collection. Slopes were represented by the unstandardized beta weights generated by these regression analyses and equaled the average change in cortisol/alphaamylase per unit time. As per standard convention in the psychoneuroendocrinology literature, a steeper, negative cortisol slope (i.e., greater decrease in cortisol per unit time) indicated a more normal rhythm, whereas a flattened (i.e., smaller decrease per unit time) or positive slope (i.e., increase in cortisol per unit time) indicated a more abnormal rhythm (Sephton et al., 2000). In the alphaamyla se literature, a n overall steep, positive slope would be consistent with an exaggerated, abnormal stress response ( Nater et al., 2007) For the exploratory aim, cortisol/alphaamylase area under the curve with respect to ground (AUCg ) was calcul ated ( Vedhar a, Tuinstra, Miles, Sanderman, & Ranchor, 2006) using a previously published trapezoidal formula (Pruessner, Kirschbaum, Meinlschmid, & Hellhammer, 2003). AUCg represented the total diurnal output of cortisol/alphaamylase and is thought to represent basa l physiological stress reactivity Statistical Analyses Descriptive statistics were calculated on all variables of interest. The distributions of cortisol and alphaamylase values were examined for normality and

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24 transformed, as needed, in order to allow for the use of parametric statistics. Due to the small sample size, the relationship between biobehavioral control variables and cortisol/alphaamylase were not examined. Analyses of Specific Aims Specific Aim 1 : To examine the relationship between wak ing levels/diurnal slopes of cortisol and alphaamylase in women with endometrial cancer. Bivariate correlation analyses were performed to estimate the effect size of the relationship between D ay 3 8 AM values of cortisol and alphaamylase and slopes of cortisol and alphaamylase The slopes of cortisol and alphaamylase were then compared using the methods of Meng, Rosenthal, & Rubin (1992) This method compares two correlated correlation coefficients In this instance, the slope for cortisol and slope for alphaamylase shared time as a predictor. Specific Aim 2 : To examine the association between perceived stress/anxiety and alphaamylase/cortisol slope in women with endometrial cancer. Bivariate correlation analyses were performed to estimate the effect sizes of the relationships between perceived stress and cortisol/alphaamylase slopes on Day 3. Parallel analyses were also performed between anxiety and cortisol/alphaamylase slopes Analysis of Exploratory Aims Exploratory Aim 3 : To explore relationships between stress/anxiety and additional markers of alphaamylase/cortisol levels (values at 8 AM, 12 PM, 5 PM, and 9 PM; and total diurnal output) in women with endometrial cancer. F or the exploratory analyses, bivariate correlation analyses w ere also performed to (a) estimate effect sizes of the relationships between stress ratings at the time of

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25 saliva collection and cortisol/alphaamylase values at each time of collection, and (b) perceived stress scores / anxiety and cortisol/alphaamylase AU Cg on Day 3.

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26 CHAPTER 3 RESULTS Preliminary Analyses Normality Assumptions Alphaamylase day 3 individual time point values were determined to be nonnormally distributed. This included values for 8 AM (Skewness = 2.417, SE = .550; Kurtosis = 7.122, SE = 1.063), 5 PM (Skewness = 2.566, SE = .550; Kurtosis = 8.182, SE = 1.063), and 9 PM (Skewness = 2.012, SE = .550; Kurtosis = 3.877, SE = 1.063). Additionally, the alphaamylase day 3 slope was nonnormally distrib uted (Skewness = 1.829, SE = .580; Kurtosis = 4.147, SE = 1.121). As a result, the Blom transformation (Blom, 1958) was used in order to normalize the data so that parametric statistics could be used. Cortisol day 3 time point values were also determined to be nonnormally distributed. This included values for 12 PM (Skewness = 2.147, SE = .616; Kurtosis = 6.147, SE = 1.191), 5 PM (Skewness = .847, SE = .616; Kurtosis = 1.508, SE = 1.191), and 9 PM (Skewness = 2.931, SE = .616; Kurtosis = 9.464, SE = 1.191). The Blom transformation was employed to normalize these data, as well. Finally, curve fit estimation was utilized to fit nontransformed cortisol and alphaamylase values to a regression line in order to obtain slopes. The resulting cortisol slope was determined to be normal; however, the alphaamylase slope was determined to be nonnormally distributed and, subsequently, the Blom transformation was used to normalize these data. Descriptive Results

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27 A total of 130 women met the eligibility requirements for participation and were subsequently enrolled in the parent study. A subset of 15 women had full psychosocial data and day 3 physiological data and were thus selected for participation in the present study Participants in the substudy ranged in age fr om 44 70 years old ( M =58.67 years SD =8.6 0 years ) and the majority of women reported that they were Caucasian ( 86. 7 %) and nonHispanic ( 80 0 %). The majority of participants in the sub study had Stage I disease (52.9%) ; however 17.6% had Stage II disease and 11.8% had Stage III disease. Additionally, 17.6% were classified as having benign endometrial disease following surgery. Of those with cancer, the primary diagnosis was endometrial adenocarcinoma, endometrioid type (58.8%). The number of days between s tudy enrollment and surgery ranged from 618 ( M =11.60, SD =3.89) and the number of days between the preoperative visit and surgery ranged from 18 days ( M =1.93, SD =1.98). Comparison to the Parent Study Sample T tests and chi square analyses indicated that there were no statistically significant differences between the group with incomplete psychosocial and physiological data ( n = 115) when compared to the group with complete psychosocial data and Day 3 physiological data ( n = 15) across age or disease stage However, significant differences were present between the two groups across histology ( 2( 12, N = 130) = 23.894, p = .021 ) and race ( 2( 2 N = 130) = 7.459, p = .024 ). With regard to histology, the majority of participants in the sample with incomplete data reported having endometrial adenocarcinoma, endometrioid type, while the sample with complete data included women with less common histologic types of endometrial

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28 cancer (Table 31) The significant difference in race between the two groups as detected by the chi square analysis is likely the result of an inaccurate inference due to the small sample size, which is illustrated in Table 32 Analyses of Specific Aims Specific Aim 1: Comparison of Alpha Amylase and Cortisol 8 AM Values/Slopes Table 3 3 shows the slope generated by regressing alphaamylase and cortisol levels on time of collection. For alphaamylase, there was a mean increase of 3.60 Units/mL per hour, while for co rtisol, there wa s a mean decrease in cortisol of 0 .01 ug/dL per hour. Figure 1 depicts the slopes for alphaamylase and cortisol following t ransformation of the unstandardized betas into standardized betas for direct comparison. As shown in Figure 1, alp ha amylase tended to have a more positive slope than cortisol. Furthermore, alphaamylase tended to have a more variable course throughout the day with general increases in levels, while cortisol steadily decreased throughout the day. Next, relationships between cortisol and alphaamylase 8 AM values and slopes were examined using bivariate correlations (Table 34 ). A moderate negative effect size correlation ( r = .3 3 5 p =.222) emerged between cortisol and alphaamylase values at 8 AM, indicating that low alpha amylase values at 8 AM were associated with high cortisol values at 8 AM. A moderate effect size correlation ( r = 389 p = .152 ) was also found between cortisol and alphaamylase slopes. However, there was no statistically significant difference between alphaamylase and cortisol slopes ( z = .86 p = 390 ) Specific Aim 2: Stress Anxiety, and Alpha Amylase/Cortisol Slopes Contrary to hypotheses, perceived stress scores were not associated with alphaamylase slope. However, a large effect size correlation was found between alpha-

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29 amylase slope and MBMD anxiety tension ( r = .722, p <.05), suggesting that women with more MBMD anxiety tension had less of an increase in alphaamylase per unit time (Table 35 ; Figure 32 ). There was a moderate effec t size correlation between greater SIGH AD anxiety and greater decrease in cortisol per unit time ( r = .507), as well as between greater MBMD anxiety tension and greater decrease in cortisol per unit time ( r = .619) (Table 3 5). In order to examine thes e relationships further, the alphaamylase and cortisol slopes of the participant with the highest MBMD anxiety tension score and the participant with the lowest MBMD anxiety tension score were graphed (Figure 32). As shown in Figure 32, the high anxiet y tension participant had a more blunted alphaamylase slope than the low anxiety tension participant, However, the high anxiety tension participant had a flatter cortisol slope than the low anxiety tension participant, overall, in spite of having an uns tandardized regression coefficient indicating a higher rate of decline across the course of the day compared to the low anxiety tension participant. Further examination indicated that this discrepancy may be due by the fact that the high anxiety tension participants cortisol nadir occurred at 12 PM, which is abnormally early. This abnormally early nadir resulted in a statistically high rate of change between 8 AM and 12 PM, followed by a statistically flattened slope across the remainder of the day. This abnormal pattern produced a more negative overall (i.e., 8 AM to 9 PM) slope compared to the low anxiety tension participant, resulting in the appearance of a more normal slope. In contrast, the low anxiety tension participants cortisol nadir occurred at 9 PM, which is the normal pattern.

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30 In addition, in contrast to the highest anxiety tension participant, the lowest anxiety tension participant experienced a relatively steady rate of decline of cortisol across the course of the day. Although this pattern resulted in a slope that is greater (more abnormal) than that of the high anxiety tension participant, the visual representation of the slope indicates that this is in fact a more normal pattern. Thus, these results are consistent with initial hypothes es. Exploratory Aim 3: Stress, Anxiety, and Other Markers of AlphaAmylase/Cortisol Levels MBMD anxiety tension demonstrated a moderate effect size correlation with lower 8 AM alphaamylase levels ( r = .406) and a large effect size correlation with lower alphaamylase AUCg ( r = .712, p < .05 ) This indicated that greater MBMD anxiety tension was associated with lower 8 AM alphaamylase and less total diurnal alphaamylase output (Table 36). Furthermore, moderate effect size correlations emerged b etween greater perceived stress and greater MBMD anxiety te nsion and greater 8 AM cortisol ( r = .437 and r = .451, respectively ) A large and significant effect size correlation also emerged between greater SIGH AD an xiety and greater 8 AM cortisol ( r = 605, p < .05 ) Stress/anxiety variables were not associated with total diurnal cortisol output (Table 36). A moderate and significant effect size correlation was found between stress ratings at 8 AM and alphaamylase levels at 12 PM ( r = .575, p < .05) suggesting that greater stress early in the morning was associated with alphaamylase levels later in the day. A m oderate effect size correlation emerged between greater stress at 8 AM and less cortisol at 5 PM ( r = .324) Finally, cortisol at 9 PM demons trated moderate effect

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31 size correlations with stress at 8 AM ( r = .360), 12 PM (r = .355 ), and 9 PM ( r = .339 ) This indicated that greater stress throughout the day was associated with increased cortisol levels at 9 PM (Table 37).

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32 Table 31. Histology distribution Parent Study Sub study Endometrial adenocarcinoma, endometrioid type 79 9 Complex endometrial hyperplasia with atypia 5 2 Complex endometrial hyperplasia without atypia 1 0 Clear cell carcinoma of endometrium 4 0 Mixed clear cell & endometrioid adenocarcinoma 1 0 Mixed serous & clear cell adenocarcinoma of endometrium 1 0 Endocervical adenocarcinoma, endometrioid type 0 1 Papillary serous carcinoma 3 1 Ovarian endometrioid carcinoma, endometrial adenocarcinoma, endometrioid type 1 0 Endometrioid adenocarcinoma with focal squamous differentiation 2 0 Endometrial adenocarcinoma with focal clear cell features 1 0 Adenomyosis 0 1 No residual tumor 0 1 Table 32. Racial distribution Parent Study Sub study Black o r African American 8 1 White 103 13 Mixed 0 1 Table 33 Regression of cortisol and alphaamylase (sAA) levels on time of collection N b sAA 17 3.60 0.24 0 Cortisol 15 0.01 0 .067 Table 34 Correlations between waking levels/diurnal slopes of c ortisol and sAA Cortisol 8 AM Cortisol slope sAA 8 AM .335 sAA slope .3 89 moderate effect size ( p = ns)

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33 Table 35 Correlations between c ortisol / sAA slopes and perceived stress / anxiety scores PSS SIGH AD Anxiety MBMD Anxiety Tension sAA slope .069 .145 .722** Cortisol slope .292 .507* .619* moderate effect size ( p = ns); ** large effect size ( p < .05) Table 36 Correlations between waking levels/total diurnal output of c ortisol and sAA perceived stress, and anxiety PSS SIGH AD Anxiety MBMD Anxiety Tension sAA 8 AM .233 .199 .406 sAA AUCG .240 .253 .712** Cortisol 8 AM .437* .605** .451* Cortisol AUCG .079 .084 .043 moderate effect size ( p = ns); ** large effect size ( p < .05) Table 37 Correlations between stress ratings at the time of collection and corresponding cortisol/sAA levels Stress 8 AM Stress 12 PM Stress 5 PM Stress 9 PM sAA 8 AM .137 sAA 12 PM .575** .067 sAA 5 PM .059 .219 .057 sAA 9 PM .177 .002 .126 .184 Cortisol 8 AM .192 Cortisol 12 PM .071 .176 Cortisol 5 PM .324 .122 .062 Cortisol 9 PM .360 .355 .132 .339 moderate effect size ( p = ns); ** large effect size (p < .05)

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34 0 50 100 150 200 250 0 5 10 15 20 25 alpha amylase cortisol Figure 31. Mean alphaamylase and cortisol slopes ( n = 15)

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35 Figure 32. sAA and cortisol slopes for high anxiety versus low anxiety participants 0.0 100.0 200.0 300.0 400.0 500.0 600.0 0 5 10 15 20 25 Low Anxiety Alpha Amylase Cortisol 0.0 100.0 200.0 300.0 400.0 500.0 600.0 0 5 10 15 20 25 High Anxiety Alpha Amylase Cortisol

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36 CHAPTER 4 DISCUSSION Previous research on cortisol has demonstrated a well established diurnal pattern in response to psychological stress that is characterized by a flatter slope signaling abnormality ( Nater et al. in 2007; Sephton et al., 2000) However, very little research has investigated the circadi an rhythm of alphaamylase in medical populations. Research has illuminated conflicting evidence for alphaamylase diurnal responses to stress and sparse associations with psychological factors, suggesting several gap s in the current literature. In sum, t he s tudy s main results indicated that alphaamylase tended to have a more positive slope than cortisol although the slopes were not statistically significantly different Secondly lower 8 AM levels of alphaamylase were associated with higher 8 AM level s of cortisol. Finally, a relationship was found between alphaamylase and cortisol slopes. These findings are consistent with the hypotheses 1a and 1b. Contrary to hypothesi s 2a perceived stress scores were not associated with alphaamylase slope. Women with more MBMD anxiety tension had les s of an increase in alphaamylase per unit time (i.e., a blunting effect). Additionally, increased SIGH AD anxiety and MBMD anxiety tension were both associated with a greater decrease in cortisol per unit time, which suggests a blunting of the cortisol response as well While the blunting of alpha amylase is contrary to hypothesis 2b, the blunting of the cortisol response is consistent with this hypothesis. These findings suggest that diurnal patterns in this sample are similar to those in published research with healthy individuals. In particular, stress and anxiety may be associated with SNS dependent alphaamylase in women with endometrial cancer.

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37 Results that emerged in the unexpected direction may demonstrate blunting of SNS activity under chronic stress, as is often seen with worn out HPA stress systems. Additionally, new discoveries of appropriate methodology for measurement of stress hormones, stress hormone profiles (particularly SNS dependent markers) and thei r impact on other physiological and psychological processes continue to emerge in the literature. Results from this study highlight the limitations associated with how the literature currently operationalizes diurnal cortisol/alphaamylase rhythm. Although the use of regression coefficients to quantify slopes is effec tive at providing estimations of change across over time, visualizing slopes using growth plots can be an important tool for confirming direction and rate of decline. Exploratory analyses asse ssing relationships between stress/anxiety and additional markers of alphaamylases/cortisol levels revealed interesting relationships; however, results have been interpreted with caution as the literature has not yet attempted to assess alphaamylase usin g independent values and stress ratings at various time points Women with more anxiety tension showed lower AM alphaamylase values and less total diurnal alphaamylase output, suggesting a possible blunting of alphaamylase throughout the day. With regar d to cortisol, higher 8 AM values and a greater decrease in cortisol per unit time were both associated with greater perceived stre ss and greater anxiety tension; however, stress and anxiety were not associated with total diurnal cortisol output. These fin dings may indicate that high levels of stress and anxiety result in a blunted, more abnormal cortisol response. Study Limitations Several limitations are present that would suggest caution when making interpretations of these results. Although the majority of published studies assessing

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38 alphaamylase have utilized small sample sizes, the statistical power associated with the results presented in this paper may be affected by a particularly small sample size. For example, a significant difference between the alphaamylase slope and the cortisol slope may actually exist; however there may not have been enough statistical power to detect this relationship. Additionally, there were significant differences in histology and race between those with complete psychosocial and physiological data and those with incomplete data. This appears to be explained by a relatively homogenous sample with regard to histology in the sample with incomplete data. For example, the breakdown of histology in the sample with incomplete data revealed that the majority of patients were classified as having endometrial adenocarcinoma, endometrioid type. In contrast, the sample with complete data demonstrated more heterogeneity across classifications. Another limitation associated with this study is the use of a modified version of the SIGH AD. This decreases the ability to generalize results from this particular questionnaire to those findings from studies using the full questionnaire. Finally, distinctions between state and trait anxiety were not evaluated in this research, which may confound statistically significant relationships found between endocrine markers and anxiety as a result of participants stable tendencies to exhibit anxious responses when faced with threatening situations. These limitations serve as important considerations for future research assessing physiological stress profiles and psychological correlates. Future Directions Future directions will emphasize the importance of increasing the sample size in order to replicat e and expand on these findings. This would also allow for the utilization of linear mixed modeling as a means of determining change over time both between

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39 and within individuals as well as a means of further comparing alphaamylase and cortisol profiles. M ost important is the need to further explore possible immune function correlates in order to gain a better understanding of how these independent stress systems directly affect immunity. A multitude of research has supported various interventions to reduce the effects of psychological stress (Reiche et al., 2005) leading to changes associated with reduced endocrine responses (Cruess et al., 2000) and ultimately improved cell mediated immunity among cancer patients. Expanding on research involving alphaamylase will hopefully support the need for interventions targeting the sympathetic nervous system stress responses, thereby improving immune function at the cellular level and slowing the progression of cancer.

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40 LIST OF REFERENCES American Cancer Society (2009). Cancer facts & figures. Atlanta, GA: American Cancer Society. Antoni, M.H., Lutgendorf, S.K., Cole, S.W., Dhabhar, F.S., Sephton, S.E., McDonald, P.G., Stefanek, M., & Sood, A.K. (2006). The influence of bio b ehavioural factors on tumour biology: Pathways and mechanisms. Nature, 6, 240 248. Beck, A.T., Steer, R.A., & Brown, G.K. (1996). BDI II manual Psychological Corporation: San Antonio, TX. Blom, G. (1958). Statistical Elements and Transformed Beta Varia bles. New York: Wiley. Bower, J.E., Ganz, P.A., & Aziz, N. (2005). Altered cortisol response to psychologic stress in breast cancer survivors with persistent fatigue. Psychosomatic Medicine, 67, 277280. Bower, J.E., Ganz, P.A., Dickerson, S.S., Peters en, L., & Fahey, J.L. (2005). Diurnal cortisol rhythm and fatigue in breast cancer survivors. Psychoneuroendocrinology 30, 92 100. Brown, G.R., Rundell, J.R., McManis, S.E., Kendall, S.N., Zachary, R., & Temoshok, L. (1992). Prevalence of psychiatric disorders in early stages of HIV infection. Psychosomatic Medicine, 54, 588601. Cohen, L., De Moor, C., Devine, D., Baum, A., & Amato, R.J. (2001). Endocrine levels at the start of treatment are associated with subsequent psychological adjustment in cancer patients with metastatic disease. Psychosomatic Medicine 63, 951958. Cohen, S., Kamarck, T., & Mermelstein, R. (1983). A global measure of perceived stress. Journal of Health and Social Behavior, 24, 385 396. Cruess, D.G., Antoni, M.H., McGregor, B.A., Kilbourn, K.M., Boyers, A.E., Alferi, S.M., Carver, C.S., & Kumar, M. (2000). Cognitive Behavioral Stress Management reduces serum cortisol by enhancing benefit finding among women being treated for early stage breast cancer. Psychosomatic Medicine, 62, 304308. Cruess, D. G., Minor, S., Antoni, M.H., & Millon, T. (2007). Utility of the Millon Behavioral Medicine Diagnostic (MBMD) to Predict Adherence to Highly Active Antiretroviral Therapy (HAART) Medication Regimens Among HIV Positive Men and Women. Journal of Personality Assessment, 89(3), 277 290. Derogatis, L.R. (1975). The affects balance scale. Clinical Psychometric Research: Baltimore, MD.

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41 Field, A. (2005). Discovering statistics using SPSS 2nd Edition. SAGE Publications Ltd.: London, England. Granger, D.A., Kivlighan, K.T., Blair, C., El Sheikh, M., Mize, J., Lisonbee, J.A., Buckhalt, J.A., Stroud, L.R., Handwerger, K., & Schwartz, E.B. (2006). amylase into studies of child health, development, and social relationships. Journal of Social and Personal Relationships, 23(2), 267 290. Granger, D.A., Kivlighan, K.T., El Sheikh, M., Gordis, E.B., & Stroud, L.R. (2007). Salivary amylase in biobehavioral research: Recent developments and applications. Annals of the New York Academy of the Sciences, 1098, 122 124. Hamilton, M. (1959). The assessment of anxiety states by rating. British Journal of Medical Psychology 32, 50 55. Hamilton, M. (1960). A rating scale for depression. Journal of Neurology, Neurosurgery, and Psychiatry 23, 5662. Jehn, C.F., Kuehnhardt, D., Bartholomae, A., Pfeiffer, S., Krebs, M., Regierer, A.C., Schmid, P., Possinger, K., & Flath, B.C. (2006). Biomarkers of depression in cancer patients. Cancer 107(11), 27232729. Kaye, J.M. & Lightman, S.L. (2005). Psychological stress and endocrine axes. In K. Vedhara & M. Irwin (Eds.), Human Psychoneuroimmunology (pp. 25 52). New York: Oxford University Press. Kumar, M., Kumar, A.M., Waldrop, D., Antoni, M.H., Schne iderman, N., & Eisdorfer, C. (2002). The HPA axis in HIV 1 infection. Journal of Acquired Immune Deficiency Syndromes, 31 S89 S93. Meng, X.L., Rosenthal, R. & Rubin, D.B. (1992). Comparing correlated correlation coefficients. Psychological Bulletin 11 1(1), 172 175. Miller, A.H., AncoliIsrael, S., Bower, J.E., Capuron, L. & Irwin, M.R. (2008). Neuroendocrineimmune mechanisms of behavioral comorbidities in patients with cancer. Journal of Clinical Oncology 26(6), 971982. Millon, T., Antoni, M., Millon, C., Minor, S., & Grossman, S. (2001). MBMD (Millon Behavioral Medicine Diagnostic) Manual (2 ed.). Minneapolis, MN: DICANDRIEN, Inc. Nakane, T., Szentendrei, T., Stern, L., Virmani, M., Seely, J., & Kunos, G. (1990). Effects of IL 1 and cortisol on adrenergic receptors, cell proliferation, and differentiation in cultured human lung tumor cells. Journal of Immunology 145, 260266.

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42 Nater, U.M. & Rohleder, N. (2009). Salivary alphaamylase as a noninvasive biomarker for the sympathetic nervous system: Current state of research. Psychoneuroendocrinology, 34, 486496. Nater, U.M., Rohleder, N., Schlotz, W., Ehlert, U., & Kirschbaum, C. (2007). Determinants of the diurnal course of salivary alphaamylase. Psychoneuroendocrinology, 32, 392401. Pruessner, J.C., Kirschbaum, C., Meinlschmid, G., & Hellhammer, D.H. (2003). Two formulas for computation of the area under the curve represent measures of total hormone concentration versus timedependent change. Psychoneuroendocrinology, 28, 916931. R eiche, E.M., Morimoto, H.K., & Nunes, S.O. (2005). Stress and depressioninduced immune dysfunction: Implications for the development and progression of cancer. International Review of Psychiatry 17(6), 515 527. Reiche, E.M., Nunes, S.O., & Morimoto, H.K. (2004). Stress, depression, the immune system and cancer. The Lancet Oncology, 5(10), 617625. Sephton, S. E., Sapolsky, R.M., Kraemer, H.C., & Spiegel, D. (2000). Diurnal cortisol rhythm as a predictor of breast cancer survival. Journal of the National Cancer Institute, 92 (12), 9941000. Spiegel, D. & Giese Davis, J. (2003). Depression and cancer: Mechanisms and disease progression. Biological Psychiatry 54, 269282. Spiegel, D., GieseDavis, J., Taylor, C.B., & Kraemer, H. (2006). Stress sensitivity in metastatic breast cancer: Analysis of hypothalamic pituitary adrenal axis function. Psychoneuroendocrinology, 31(10), 12311244. Thaker, P.H., Lutgendorf, S.K., & Sood, A.K. (2007). The neuroendocrine impact of chronic stress on cancer. Cell Cycle, 6 (4), 430 433. Turner Cobb, J.M., Sephton, S.E., Koopman, C., BlakeMortimer, J., & Spiegel, D. (2000). Social support and salivary cortisol in women with metastatic breast cancer. Psychosomatic Medicine, 62, 337345. van Veen, J.F., van Vliet, I.M., DeRijk, R.H., van Pelt, J., Mertens, B., & Zitman, F.G. (2008). Elevated alpha amylase but not cortisol in generalized social anxiety disorder. Psychoneuroendocrinology, 33 1313 1321.

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43 Vedhara, K., Miles, J., Bennett, P., Plummer, S., Tallon, D., Brooks, E., Gale, L., Munnoch, K., Schreiber Kounine, C., Fowler, C., Lightman, S., Sammon, A., Rayter, Z., & Farndon, J. (2003). An investigation into the relationship between salivary cortisol, stress, anxiety and depression. Biological Psychology 62, 8996. Vedhara, K., Tuinstra, J., Miles, J. N., Sanderman, R., & Ranchor, A. V. (2006). Psychosocial factors associated with indices of cortisol production in women with breast cancer and controls. Psychoneuroendocrinology, 31(3), 299311. Williams, J.B. (1988). A structured interview guide for the Hamilton Depression Rating Scale. Archives of General Psychiatry, 45, 742 747.

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44 BIOGRAPHICAL SKETCH Stephanie Garey graduated with honors from Towson Universit y in 2007, where she received a Bachelor of Science degree in psychology. During her four years at this institution, she worked as a research assistant on several research studies, including a longitudinal study assessing attachment styles and stable self esteem evaluations. Stephanie also completed an undergraduate thesis on the associations between perceived social support, level of self esteem, and depression in college students. During her senior year, Stephanie completed two internships, including a research assistantship at the Uniformed Services University of the Health Sciences (USUHS) and a clinical assistantship on the Neurobehavioral Unit at the Kennedy Krieger Institute at Johns Hopkins. Her academic excellence and her involvement in research, teaching, and clinical work was recognized by the Towson University Department of Psychology through her receipt of a Departmental Achievement Award. After graduation, Stephanie worked as a full time research coordinator on a NIH funded study assessing biobehavioral predictors of heart failure conducted jointly at the USUHS and University of Maryland Medical Center. Stephanie began attending graduate school at the University of Florida in the Department of Clinical and Health Psychology in August 2008. She is focusing her research on psychooncology, psychoneuroimmunology, and womens health. She is currently pursuing her doctorate in clinical psychology.