Gibson, Carolyn J. MPH, MS; Joffe, Hadine MD, MSc; Bromberger, Joyce T. PhD; Thurston, Rebecca C. PhD; Lewis, Tené T. PhD; Khalil, Naila PhD; Matthews, Karen A. PhD
From the Departments of Psychology, Epidemiology, and Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania; the Center for Women's Mental Health, Massachusetts General Hospital, Boston, Massachusetts; the Department of Epidemiology & Public Health, Yale University School of Medicine, New Haven, Connecticut; and the Department of Community Health, Wright State University, Kettering, Ohio.
For a list of other members who participated in the Study of Women's Health Across the Nation (SWAN), see the Appendix online at http://links.lww.com/AOG/A297.
SWAN has grant support from the National Institutes of Health (NIH), DHHS, through the National Institute on Aging (NIA), the National Institute of Nursing Research (NINR) and the NIH Office of Research on Women's Health (ORWH) (Grants NR004061; AG012505, AG012535, AG012531, AG012539, AG012546, AG012553, AG012554, AG012495). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIA, NINR, ORWH or the NIH.
The authors thank Elizabeth Votruba-Drzal, PhD, for statistical assistance, the study staff at each site, and all the women who participated in SWAN.
Presented in part at the 22nd North American Menopause Society Annual Meeting, September 21–24, 2011, Washington, DC.
Corresponding author: Carolyn J. Gibson, Department of Psychology, University of Pittsburgh, Pittsburgh, PA 15213; e-mail: firstname.lastname@example.org.
Financial Disclosure Dr. Joffe has received research support from Bayer HealthCare Pharmaceuticals and has performed advisory and consulting work for Sanofi-Aventis/Sunovion, Pfizer, and Noven. The other authors did not report any potential conflicts of interest.
More than one-third of women in the United States have had a hysterectomy by the age of 60. This common surgery is performed on 600,000 women in the United States each year,1 accompanied by bilateral oophorectomy in 55–80% of cases.2 An association between negative mood and hysterectomy is supported by cross-sectional studies, which suggest that women with a hysterectomy, regardless of oophorectomy status, are more distressed than age-matched peers without a hysterectomy.3,4
Investigations of the potential influence of hysterectomy and oophorectomy on mood are limited and mixed.5–7 Existing studies do not generally account for mood in the years before presentation for surgery, and typically they compare the effect of hysterectomy with bilateral oophorectomy only with hysterectomy alone. Follow-up is generally short, providing mixed results about the effects of oophorectomy or hysterectomy on mood in the months and initial years after surgery.5,6 It therefore remains unclear whether any change in mood is attributable to hysterectomy or oophorectomy, and whether any changes are different than would be expected with natural menopause. In this study, we sought to examine the course of depressive and anxiety symptoms among women in midlife before and after natural menopause, hysterectomy with ovarian conservation, and hysterectomy with bilateral oophorectomy.
MATERIALS AND METHODS
Participants were from the Study of Women's Health Across the Nation, a multi-site community-based prospective study designed to examine the physical and psychological health of women as they undergo the menopausal transition. At baseline, all participants had an intact uterus and at least one ovary and met the following additional eligibility criteria: age 42–52 years; not pregnant; not using reproductive hormones; and having one or more menstrual cycles in the 3 months before the interview. Details of the design and recruitment procedures have been reported elsewhere.8 Seventy-three percent of the women selected were contacted and provided information to determine eligibility; 51% (n=3,302) of eligible women enrolled. The study enrollment period was from 1996 to 1997, and participants continue to return to their local site facility annually for interviewer-administered and self-administered questionnaires, a fasting blood draw, and reassessments of physical measures. The study was approved by the Institutional Review Boards at each site, and each participant provided written informed consent.
Depressive symptoms were assessed by trained interviewers at each annual visit using the Center for Epidemiological Studies Depression Scale, a 20-item depression symptom scale.9,10 Anxiety was assessed at each annual visit with four questions asking about the number of days in the 2 weeks before the baseline visit in which participants reported “irritability or grouchiness,” “feeling tense or nervous,” “heart pounding or racing,” or “feeling fearful for no reason.”
Menopausal status and the occurrence of hysterectomy and oophorectomy were assessed annually. Women were categorized as naturally postmenopausal if they reported a complete absence of menstrual bleeding in the previous 12 months. Participants were categorized as having had a hysterectomy with ovarian conservation if they reported hysterectomy without oophorectomy or with one ovary removed before becoming naturally postmenopausal. Participants were categorized as having had a hysterectomy with bilateral oophorectomy if they reported a hysterectomy and both ovaries removed, or both ovaries removed without hysterectomy, before becoming naturally postmenopausal.
All covariates were selected on the basis of previously documented associations with negative mood symptoms in midlife and included race, educational attainment, menopausal status the year before final menstrual period or surgery, and age the year before final menstrual period or surgery, as well as annual measurements of body mass index (BMI, calculated as weight (kg)/[height (m)]2), self-rated health, hormone therapy use, and antidepressant use. Race and educational level were self-reported in the screening interview. Final menstrual period date was based on participant self-report; if final menstrual period date was unknown, then it was set as 12 months before the date of the annual visit participants were first categorized postmenopausal. Menopausal status was assessed by self-reported bleeding patterns annually and drawn from the annual visit before each participant's final menstrual period or surgery date. Age was calculated from the participant's date of birth and date of final menstrual period or surgery. Body mass index was calculated at each annual visit. Self-rated health was assessed at each annual visit by response to the following question: “In general, would you say your health is excellent, very good, good, fair, or poor?”11 Antidepressant use and hormone therapy use were self-reported at each annual visit.
A total of 1,970 women, including 1,793 women who reached natural menopause, 76 women who had a hysterectomy with ovarian conservation, and 101 women who had a hysterectomy with bilateral oophorectomy comprised the analytic sample. Data from women who did not report hysterectomy or reach natural menopause (n=920) during their participation in the Study of Women's Health Across the Nation, those who had a hysterectomy after having been categorized naturally postmenopausal (n=32), those who reported hysterectomy in the presence of known or suspected endometrial, uterine, or ovarian cancer (n=21), those who did not have data regarding depressive or anxiety symptoms from at least one annual visit after final menstrual period or surgery (n=51), and women from the New Jersey site, subject to systematically fewer annual observations because of an early discontinuation for reasons unrelated to scientific integrity (n=131), were also excluded from this analysis. Compared with the women who were excluded from analysis, women in analytic sample were older (mean 46.3 and standard deviation [SD] 2.6 compared with mean 45.2 and SD 2.7; P<.001), more educated (46.5% compared with 37.3% college or postcollege; P<.001), reported better self-rated health (61.3% compared with 52.6% excellent or very good health; P<.001), and had a lower mean BMI (28.0 and SD 7.3 compared with 28.8, SD 7.1; P<.01) at baseline (data not shown in tables).
Racial differences in the prevalence and age at hysterectomy are documented,1 although racial differences in the effect of hysterectomy and oophorectomy have not been well-studied. To assess potential interactions between hysterectomy status and race, a secondary analysis was performed in a sample restricted to only African American and white women (n=1,581). The restricted sample included 1,422 women who reached natural menopause, 71 women who had a hysterectomy with ovarian conservation, and 88 women who had a hysterectomy with bilateral oophorectomy.
Baseline characteristics were compared using χ2 and multinomial regression for categorical variables, and analysis of variance and Bonferroni correction for continuous variables using SPSS 17. Site, race and ethnicity, age at final menstrual period or surgery, educational attainment, and menopausal status the year before final menstrual period or surgery were included as covariates in final models based on a priori decisions. Preliminary analyses were conducted to assess independent associations between annual observations of antidepressant use, hormone therapy use, self-rated health, and BMI with depressive symptoms and anxiety. These time-varying covariates were retained in final models if they were associated with depressive symptoms or anxiety in otherwise unadjusted models at P<.05.
Piece-wise hierarchical linear growth models were used to estimate the mean rate of change in depressive and anxiety scores leading up to and after final menstrual period or surgery, with annual observations nested within women (HLM for Windows 68). Hierarchical linear modeling was used because of its utility in accounting for the dependence of repeated correlated observations within individuals. Piece-wise hierarchical linear growth models were used to allow for the possibility of different mean growth trajectories before compared with after final menstrual period or surgery.12 The intercept was set as the first annual visit after final menstrual period or surgery, with estimates of the mean rate of change in mood symptoms modeled from baseline to intercept, and from intercept to the end of observations. Depressive symptoms and anxiety were modeled separately. The intercept and each growth trajectory were modeled as a function of hysterectomy status (hysterectomy with ovarian conservation or hysterectomy with bilateral oophorectomy), with natural menopause set as the referent. All predictors and covariates were entered simultaneously in the final multivariate models. For all analyses, P<.05 (two-tailed) was considered statistically significant.
Participants were followed-up for up to 10 years after baseline, with observations from up to 9 years before and after final menstrual period or surgery. Characteristics of the sample are in Table 1. Women who reported hysterectomy with or without ovarian conservation during the observed period differed significantly at baseline from women who reached natural menopause and did not have a hysterectomy over the observed period (Table 1). Naturally postmenopausal women were less likely to be African American, less likely to ever use hormone therapy over the observed period, and more likely to be older at baseline. Naturally postmenopausal women were also less likely than women with hysterectomy with ovarian conservation to have used an antidepressant over the observed period and had a lower BMI at baseline. No significant differences were seen at baseline between women who subsequently had a hysterectomy with compared with without ovarian conservation.
Depressive symptoms declined before final menstrual period or surgery and continued to decline after final menstrual period or surgery (Table 2, row for slopes). The Center for Epidemiological Studies Depression Index means were 0.72 SD lower 5 years after final menstrual period or surgery. Regardless of whether ovaries were conserved, hysterectomy status had no effect on depressive symptoms at the first annual visit after final menstrual period or surgery or on the trajectory of depressive symptoms leading up to or after final menstrual period or surgery (Fig. 1). There was no significant difference in the mean rate of change in depressive symptoms in these groups relative to natural menopause. Depressive symptoms at the first annual visit after final menstrual period or surgery varied by site, were higher among women with missing menopausal status at visit before final menstrual period or surgery, and were lower among women with at least a 4-year college education and older age at final menstrual period or surgery. The Center for Epidemiological Studies Depression Index scores were higher at visits when women were using antidepressant medications and reported poorer health and were lower at visits when women used hormone therapy.
Anxiety scores did not change significantly in the years leading up to final menstrual period or surgery, but they decreased during the period after final menstrual period or surgery (Table 2, row for slopes). Regardless of whether ovaries were conserved, hysterectomy status had no effect on anxiety symptoms at the first annual visit after final menstrual period or surgery or on the trajectory of anxiety symptoms after final menstrual period or surgery (Fig. 2). Mean anxiety scores were 0.67 SD lower 5 years after final menstrual period or surgery. Anxiety symptoms at the first annual visit after final menstrual period or surgery varied by site, were higher among women with missing menopausal status at the visit before final menstrual period or surgery, were lower among African American women and Chinese women, and tended to be lower among women who were older at final menstrual period or surgery. Anxiety scores increased concurrently with antidepressant use and poorer self-rated health and decreased with hormone therapy use.
In the subsample of only African American and white women, the results were similar to the overall sample results. However, African American women who had a hysterectomy with ovarian conservation experienced a steeper decline in depressive symptoms leading up to surgery than did white women who had a hysterectomy with ovarian conservation, (estimates=−.20 and P<.001 compared with −.47 and P<.03). Although all other women had a decrease in anxiety symptoms leading up to surgery and final menstrual period (Beta coefficient=−.03, P<.01), African American women with natural menopause had an increase in anxiety symptoms during this time (Beta coefficient=.04, P=.02).
In sensitivity analyses conducted to examine the role of hormone therapy use, the mean rate of change in depressive and anxiety symptoms was equivalent in the full sample, among women who reported hormone therapy use after final menstrual period or surgery, and among women who did not report hormone therapy use after menstrual period or surgery (data not shown).
This study assessed change in mood symptoms after surgical menopause relative to natural menopause. We found that both depressive and anxiety symptoms generally improved over the course of the menopausal transition for all women, with no effect of hysterectomy status on this change. Our results suggest that compared with natural menopause, hysterectomy with or without ovarian conservation among women in midlife does not have a lasting negative effect on mood.
These results are consistent with studies examining mood symptoms over a short follow-up period after hysterectomy; some studies, although not all, suggest that mood symptoms improve after surgery.5,6 In contrast to our data suggesting a continual decline in symptoms over time, Rocca et al7 showed an increased long-term risk of de novo anxiety and depressive symptoms among women with hysterectomy with bilateral oophorectomy a median of 24 years after surgery. However, mood symptoms and their timing in that study were assessed retrospectively from women interviewed years or decades after surgery and may have been subject to retrospective reporting biases. Women in that study also experienced hysterectomy at a variety of ages, whereas this investigation examines only women with hysterectomy during midlife and before the onset of natural postmenopause. Health and mental health risks of oophorectomy may be limited to younger women who have not already begun to experience hormonal changes related to the progression to natural menopause.13
Additional findings about annually measured hormone therapy and antidepressant use are worth mentioning. Use of hormone therapy was concurrently associated with lower levels of anxiety and depressive symptoms. Hormones were used at some point over the observation by the majority of participants and, as expected, were particularly common among women with a hysterectomy and oophorectomy. Excluding women who reported after final menstrual period or surgery hormone therapy use did not affect the trajectory of changes in depressive or anxiety symptoms, suggesting that although hormone therapy was associated with improvements in mood, it did not account for the general lack of relationship seen between mood trajectories postsurgery and hysterectomy status. Antidepressant or anxiolytic use was strongly and consistently concurrently related to higher anxiety and depressive symptoms, which may highlight the need for clinicians to appropriately monitor treatment efficacy among patients in midlife presenting with mood symptoms.
Several limitations of this study should be noted. These results are based on assessment of anxiety and depressive symptoms and may not be generalizable to populations with anxiety and depressive disorders. Women who chose to participate in this study and continue to participate in annual visits may differ from women in the general population, and women who reported hysterectomy during the observed period may differ from women with a hysterectomy in the general population. In a survey of 15,160 women screened for study participation, women with previous hysterectomy were more often African American, less educated, older, separated or widowed or divorced, multiparous, current or past smokers, and religious.14 Thus, the remaining sample of eligible women tended to differ on those potential risk factors for hysterectomy than the sample contacted for survey and eligibility.8
Despite these limitations, the study also had considerable strengths. A large, well-characterized, multi-ethnic, population-based sample of women in midlife was used, providing information about symptom experience among women from diverse backgrounds. Data were collected over an 11-year period, allowing for observations across a range of participant ages and stages in the menopausal transition. This study was unique in prospectively evaluating mood and hysterectomy status, providing information on the influence of elective hysterectomy with and without bilateral oophorectomy on depressive and anxiety symptoms over time while accounting for mood symptoms before surgery. The comparison of these trajectories with those of naturally postmenopausal women offers needed information not only on the effects of oophorectomy over hysterectomy alone but also on how these differ from general trends experienced over the natural menopausal transition.
Overall, the results of this study should provide reassurance to women and their clinicians about the progression of depressive and anxiety symptoms in women both before and after menopause. Clinicians should be aware that negative mood symptoms generally decline over time over the course of the menopausal transition,15 suggesting that anxiety and depressive symptoms should improve as women enter the postmenopausal years. Lasting effects on both anxiety and depressive symptoms do not appear to be necessary considerations when evaluating decisions surrounding ovarian conservation.
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