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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Low Genit Tract Dis. Author manuscript; available in PMC Jan 1, 2012.
Published in final edited form as:
PMCID: PMC3084664
Impact of stress and depression on the frequency of squamous intraepithelial lesions
L. Stewart Massad, M.D.
Washington University School of Medicine, St. Louis, MO
Denis Agniel, MS
The CORE Center at John Stroger Hospital of Cook County, Chicago, IL
Howard Minkoff, M.D.
Maimonides Medical Center, Brooklyn, NY
D. Heather Watts, M.D.
Eunice Kennedy Shriver National Institute for Child Health and Human Development, Bethesda, MD
Gypsyamber D'Souza, Ph.D.
Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
Alexandra M. Levine, M.D.
City of Hope National Medical Center, Duarte, CA, and Keck School of Medicine, University of Southern California, Los Angeles, CA
Teresa M. Darragh, M.D.
University of California, San Francisco, CA
Mary Young, M.D.
Georgetown University School of Medicine, Washington, DC
Anthony Cajigas, MD
Montefiore Medical Center, Bronx, NY
Kathleen Weber, B.S.N
The CORE Center at John Stroger Hospital of Cook County, Chicago, IL
Contact Dr. Massad at: Division of Gynecologic Oncology, 4911 Barnes-Jewish Hospital Plaza, St. Louis, MO 63110. Tel: 314-362-3181. Fax: 314-362-2893. massadl/at/
To explore previously reported associations between cervical squamous lesions and psychological measures of stress and depression.
In a multicenter cohort study, HIV infected and seronegative comparison women had Pap tests and completed self-report questionnaires including the Perceived Stress Scale-10 (PSS), which measures perceived stress; the PTSD Civilian Symptom Checklist (PCL-C), which measures symptoms of posttraumatic stress disorder; and the Center for Epidemiologic Studies Depression Scale (CES-D), which measures depressive symptoms.
Median scores were 13 (range 0–38) for the PSS, 24 (range 17–85) for the PCL-C, and 8 (range 0–57), for the CES-D, indicating moderate stress and minimal depression. For PSS, compared to women in the lowest tertile of reported stress, O.R. for SIL was 0.88 (95% C.I. 0.50–1.54) for women in the middle tertile and 0.96 (95% C.I. 0.54–1.68) for women in the highest tertile. For PCL-C, compared to women in the lowest tertile of PTSD symptoms, O.R. for SIL was 0.79 (95% C.I. 0.43–1.41) for women in the middle tertile and 1.17 (95% C.I. 0.68–2.01) for women in the highest tertile. SIL rates were similar for CES-D scores ≥16 (compared to women with lower scores O.R. 1.41, 95% C.I. 0.88–2.26) and ≥ 23 (O.R. 1.39, 95% C.I. 0.81–2.40). In multivariable analysis including number of sexual partners, age, income, ethnicity, and serostatus, stress as measured by PSS and PCL-C, and depressive symptoms as measured by CES-D remained unassociated with SIL.
We found no evidence that stress and depression affect the prevalence of cervical squamous lesions.
Keywords: stress, depression, cervical lesion, Papanicolaou test
Abnormal Pap results (squamous intraepithelial lesions, or SILs) are common among women with the human immunodeficiency virus (HIV) (1, 2). Risk factors for abnormal Pap tests include younger age, smoking, number of sexual partners, prior abnormal Pap, and prior cervical disease treatment. However, immune impairment is a crucial factor predicting abnormal cytology. HIV serostatus, CD4 count, and HIV RNA level have been linked to abnormal Pap results, and use of highly active antiretroviral therapy (HAART) may be protective (3).
Stress is a poorly understood potential risk factor for cervical disease. Several authors have suggested that stress increases risk for abnormal Pap results (46), and stress management may decrease risk for cervical disease in HIV seropositive women (7). Stress may act on the cervix through modulation of immune function, as the human papillomavirus (HPV), which causes cervical cancer and its precursor, cervical intraepithelial neoplasia (CIN), is often cleared by host immunity (8). The impact of stress on genital immunity is illustrated by its enhancement of herpes reactivation (9) and bacterial vaginosis (1012). Greater stress has been linked to decrements in measures of cellular immunity in individuals with HIV (1316), though HAART may ameliorate these effects (17). Stress has also been linked to impaired T-cell response to HPV16, the most virulent genotype of HPV (18). Since cervical cancer prevention requires compliance with screening and treatment protocols, stress may promote the persistence and prevalence of cervical lesions when it interferes with screening and follow-up (19, 20).
However, most studies of the relationship between stress and cervical disease have been small, making it difficult for them to control for potential confounders. We set out to estimate the independent significance of any association between life stress and cytologic findings of squamous intraepithelial lesions (SILs) and to determine the impact of HIV serostatus on that association in a large cohort of women.
This investigation was part of the Women's Interagency HIV Study (WIHS), a continuing multicenter prospective cohort study of the health of HIV seropositive women and at-risk HIV-uninfected comparison women in the United States. The protocols, recruitment processes, procedures, and baseline results of the WIHS have been previously described (21). Enrollment began in 1994 at 6 study consortia (Brooklyn, Bronx, Chicago, Los Angeles, San Francisco, and Washington, D.C.) and was expanded to 3,766 women during 2001–2002 to recruit younger women (22). Written informed consent was obtained after local human subjects committees approved. Follow-up continues, but this analysis includes only information obtained between October 1, 2008 and March 30, 2009.
Information on demographics, behavior, and health was obtained via interview every six months, along with a physical examination and Pap test. HIV status was established by Western blot, and for women who seroconverted during study serostatus was assigned according to results at the visit at which Pap test and stress assessments were obtained. Pap tests were interpreted centrally at Dianon (New York, NY, formerly Kyto or Kyto Meridien) according to the 1991 Bethesda system for classification of cervicovaginal cytology (23). All Pap smears were screened by two cytotechnologists blinded to HIV status, with 10% of all negative smears and all abnormal smears reviewed by a cytopathologist. Our outcome variable was a Pap result of SIL or cancer at the study visit coinciding with administration of the stress questionnaires. We excluded 256 women with atypical squamous cells of undetermined significance and 7 with atypical glandular cells.
Participants completed the Perceived Stress Scale-10 (PSS) (24, 25), which measures individuals' perception of stress and coping, the PTSD Civilian Symptom Checklist (PCL-C) (26), and the Center for Epidemiologic Studies Depression Scale (CES-D) (27), which measures depressive symptoms. Scores on the PSS-10 were converted to tertiles for comparison, while women with PCL-C scores over 50 were considered to have post-traumatic stress. Scores on the CES-D above 15 reflect a moderate prevalence of clinical depression (28).
Less than 1% of observations were missing values on covariates; these were inputted using medians for continuous variables and modes for discrete variables. Descriptive comparisons of covariates with stress tertiles were conducted using Pearson's chi-squared test. Univariate and multivariate odds ratios for SIL were determined using logistic regression with Wald confidence intervals. Multivariate logistic models were checked using bootstrapping methods. All analyses were performed in R.
The demographic characteristics of our study group are shown in Table 1. Participants were predominantly of minority ethnicity and of low income. Almost 15% had abnormal Pap test results, although most of these were atypical or low grade.
Table 1
Table 1
Demographic characteristics of 1536 women completing stress assessments divided into by tertiles of stress score.
Median score for the PSS-10 perceived stress measure was 13 (range 0–38) and for the PCL-C was 24 (range 17–85), suggesting moderate stress. As shown in Table 1, stress as measured by PSS was associated with older age, lower income, less education, smoking, and drug use. PSS and PCL-C were correlated (P < 0.001 by test for nonzero correlation). Of the 1536 women with completed questionnaires, PCL-C scores were >50, indicating post-traumatic stress, for 149 (10%). Median CES-D score was 8 (range 0–57), suggesting minimal prevalence of depression. CES-D score was also correlated with PSS (P < 0.001).
In univariate analysis, SIL was associated with known cervical cancer risk factors, including HIV seropositivity (O.R. 12.62, 95% C.I. 3.96–40.27, P < 0.001, compared to seronegative women), ethnicity (O.R. 0.38, 95% C.I. 0.19–0.79, P = 0.004 for white and O.R. 0.46, 95% C.I. 0.23–0.95, P = 0.026, for other ethnicity compared to African-American), current employment (O.R. 0.28, 95% C.I. 0.15–0.51, P < 0.001 for compared to unemployed women), and current smoking (O.R. 3.24, 95% C.I. 1.71–6.15, P < 0.001, compared to never smokers).
The proportion of women with SIL was not significantly different across stress levels. For PSS, compared to women in the lowest tertile of reported stress, O.R. for SIL was 0.88 (95% C.I. 0.51–.53, P = 0.655) for women in the middle stress tertile and 0.96 (95% C.I. 0.55–1.68, P = 0.886) for women in the highest stress tertile. For PCL-C, compared to women in the lowest tertile of reported PTSD symptoms, O.R. for SIL was 0.78 (95% C.I. 0.44–1.40, P = .415) for women in the middle tertile and 1.17 (95% C.I. 0.69–2.00, P = .560) for women in the highest stress tertile.
Depressive symptoms also were not associated with SIL. SIL rates were similar for CES-D scores above 16 (O.R. 1.41, 95% C.I. 0.88–2.26, P = 0.152) and above 23 (O.R. 1.39, 95% C.I. 0.81–2.40, P = 0.244).
Because prior treatment might have masked significant associations, we repeated analyses to look for a possible correlation between SIL at any time during WIHS and either PSS or PCL-C at the index visit; again no association was found (not shown). Similarly, repeating subset analyses in only the HIV seropositive group did not reveal an association between stress and SIL (not shown). Because HIV-related immunosuppression may have dominated stress as a determinant of SIL, we repeated analyses, limiting assessment only to those women with HIV and CD4 lymphocyte counts >500 and to women without HIV; no association between SIL and PSS score, PCL-C, or CES-D was found. Finally, we found no associations between SIL and combinations of PCL-C and CES-D scores or potentially stressful events including trauma history and self-reported sexual abuse (not shown).
Results of multivariable analysis are shown in Table 2. Odds of SIL were elevated among women with HIV infection and were linked to degree of immunosuppression, race, and current smoking. PSS, PCL-C score >50, and CES-D score >15 were not significantly associated with SIL.
Table 2
Table 2
Multivariable analysis of associations of demographic and biological risk factors for squamous intraepithelial lesions on Pap testing.
We failed to find an association between prevalent SIL and validated measures of perceived stress, post-traumatic stress, or depressive symptoms, despite previous studies that identified stress as a correlate of abnormal Pap results. Since both stress and SIL are linked to minority ethnicity and measures of socioeconomic status, residual confounding may explain prior findings. Alternatively, we may have failed to identify a link because we had relatively few women with low stress levels. In our high-risk population, other known risks for SIL such as smoking, HIV-related immunosuppression, and multiple sexual partners may dominate any effects of stress. In addition, we assessed stress at a single time point while cervical disease commonly develops over many years, and so we cannot exclude an effect of chronic stress on SIL risk. Finally, our population had been screened and incident cervical cancer precursors treated over many years; stress may have a greater impact on SIL in an unscreened population. However, current stress was not associated with ever having had SIL during our participants' 15-year history of follow-up.
While interventions to minimize life stress may improve quality of life, cervical cancer prevention efforts should remain focused on screening and treatment of precursor lesions. In addition, while stress may not impact SIL risk, it may impair compliance with screening and follow-up among women at risk for cervical cancer. Clinical trials to assess the effect of stress reduction efforts on cervical disease and compliance may improve our understanding of the relationship between stress and cervical cancer risk.
Data in this manuscript were collected by the Women's Interagency HIV Study (WIHS) Collaborative Study Group with centers (Principal Investigators) at New York City/Bronx Consortium (Kathryn Anastos); Brooklyn, NY (Howard Minkoff); Washington DC Metropolitan Consortium (Mary Young); The Connie Wofsy Study Consortium of Northern California (Ruth Greenblatt); Los Angeles County/Southern California Consortium (Alexandra Levine); Chicago Consortium (Mardge Cohen); Data Coordinating Center (Stephen Gange). The WIHS is funded by the National Institute of Allergy and Infectious Diseases (UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, and UO1-AI-42590) and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (UO1-HD-32632). The study is co- funded by the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute on Deafness and Other Communication Disorders. Funding is also provided by the National Center for Research Resources (UCSF-CTSI Grant Number UL1 RR024131). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.
Source of funding: NIH and others
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