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Use of antidepressants following hysterectomy with or without oophorectomy: A national sample in the US

  • L.J. Li
    Affiliations
    Department of Neuropsychiatry, Behavioral Neurology, and Clinical Psychology, Beijing Tian Tan Hospital, Capital Medical University, Beijing, China

    China National Clinical Research Centre for Neurological Diseases, Beijing, China

    Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China

    Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
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  • Q. Chen
    Affiliations
    Department of Neuropsychiatry, Behavioral Neurology, and Clinical Psychology, Beijing Tian Tan Hospital, Capital Medical University, Beijing, China

    China National Clinical Research Centre for Neurological Diseases, Beijing, China

    Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China

    Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
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  • N. Zhang
    Affiliations
    Department of Neuropsychiatry, Behavioral Neurology, and Clinical Psychology, Beijing Tian Tan Hospital, Capital Medical University, Beijing, China

    China National Clinical Research Centre for Neurological Diseases, Beijing, China

    Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China

    Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China

    Department of Psychology, Capital Medical University, Beijing, China
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  • X. Yao
    Correspondence
    Correspondence to: X. Yao, 711 Concession Street, Hamilton L8V 1C3, ON, Canada.
    Affiliations
    Department of Health Research Methods Evidence and Impact, McMaster University, Hamilton, Ontario, Canada

    Center for Clinical Practice Guideline Conduction and Evaluation, Children's Hospital of Fudan University, Shanghai, China
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  • C.X. Wang
    Correspondence
    Correspondence to: C.X. Wang, No. 119 South Fourth Ring West Road, Fengtai District, Beijing 100070, China.
    Affiliations
    Department of Neuropsychiatry, Behavioral Neurology, and Clinical Psychology, Beijing Tian Tan Hospital, Capital Medical University, Beijing, China

    China National Clinical Research Centre for Neurological Diseases, Beijing, China

    Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China

    Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
    Search for articles by this author
Open AccessPublished:September 29, 2022DOI:https://doi.org/10.1016/j.maturitas.2022.09.010

      Highlights

      • Hysterectomy, with or without oophorectomy, was found to be positively associated with antidepressant use.
      • A positive association between hysterectomy without oophorectomy and antidepressant use was found among non-Hispanic white women and women of other races (i.e., Hispanic, Asian, and multi-racial).
      • A positive association between hysterectomy with oophorectomy and antidepressant use was found among non-Hispanic black women.

      Abstract

      Objective

      Hysterectomy is one of the most common gynecological surgeries conducted around the world. Previous studies reported inconsistent results on depressive symptoms experienced after hysterectomy. This study explored the association between hysterectomy with or without oophorectomy and the use of antidepressants.

      Study design

      This cross-sectional study included 4888 subjects between 20 and 80 years old who participated in the US National Health and Nutrition Examination Survey (NHANES) between 2015 and 2018. The associations between hysterectomy with or without oophorectomy and the use of antidepressants were estimated using multivariable logistic regression models.

      Main outcome measures

      There was a positive relationship between hysterectomy, both with and without oophorectomy, and the use of antidepressants after adjusting for all potential confounders (OR = 2.13, 95 % CI = 1.43–3.17, p = 0.000; OR = 2.04, 95 % CI = 1.35–3.06 p = 0.001). In the subgroup analysis stratified by race, a positive association between hysterectomy without oophorectomy was found among non-Hispanic white women (OR = 1.89, 95 % CI = 1.04–3.44, p = 0.038) and women of other races (OR = 3.14, 95 % CI = 1.30–7.56, p = 0.010), and a positive association between hysterectomy with oophorectomy was found among non-Hispanic black women (OR = 3.09, 95 % CI = 1.15–8.27, p = 0.024). However, no association was found among non-Hispanic black and Mexican American women who had undergone hysterectomy with oophorectomy, and it was not reported in women of non-Hispanic white, Mexican American or other race who underwent hysterectomy with oophorectomy.

      Conclusion

      This study suggested that hysterectomy was significantly associated with antidepressant use, but the extent of the associations may vary by race.

      Abbreviations:

      NHANES (National Health and Nutrition Examination Survey), NCHS (National Center for Health Statistics), DLQ (disability questionnaire), PHQ-9 (The 9-item Patient Health Questionnaire), OR (odds ratio), CI (confidence intervals), SD (standard deviation), STROBE (The STrengthening the Reporting of OBservational studies in Epidemiology), FSH (Follicle Stimulating Hormone), MHT (menopausal hormone therapy)

      Keywords

      1. Introduction

      Hysterectomy, with or without oophorectomy, is one of the most common gynecological surgeries worldwide [
      • Wright J.D.
      • Herzog T.J.
      • Tsui J.
      • Ananth C.V.
      • Lewin S.N.
      • Lu Y.S.
      • Neugut A.I.
      • Hershman D.L.
      Nationwide trends in the performance of inpatient hysterectomy in the United States.
      ]. More than 33 % of US women have undergone this operation by the age of 60 years old due to abnormal uterine bleeding, uterine fibroids or other benign gynecological disorders and gynecologic malignancies [
      • Wu J.M.
      • Wechter M.E.
      • Geller E.J.
      • Nguyen T.V.
      • Visco A.G.
      Hysterectomy rates in the United States, 2003.
      ,
      • Jacoby V.L.
      • Vittinghoff E.
      • Nakagawa S.
      • Jackson R.
      • Richter H.E.
      • Chan J.
      • Kuppermann M.
      Factors associated with undergoing bilateral salpingo-oophorectomy at the time of hysterectomy for benign conditions.
      ,
      • Backes F.J.
      • Fowler J.M.
      Hysterectomy for the treatment of gynecologic malignancy.
      ]. It has been reported that women living in the Unites States have the highest cumulative risk throughout their lifetime [
      • Mcpherson K.
      • Gon G.
      • Scott M.
      International variations in a selected number of surgical procedures[J].
      ], and about 54 % of women who underwent hysterectomy also had their bilateral ovaries removed [
      • Whiteman M.K.
      • Hillis S.D.
      • Jamieson D.J.
      • Morrow B.
      • Podgornik M.N.
      • Brett K.M.
      • Marchbanks P.A.
      Inpatient hysterectomy surveillance in the United States, 2000–2004.
      ].
      Although hysterectomy is a valid option for treating benign gynecological conditions, it is an intrusive surgical procedure with numerous side-effects, such as bleeding and reduced physical functioning [
      • Warren L.
      • Ladapo J.A.
      • Borah B.J.
      • Gunnarsson C.L.
      Open abdominal versus laparoscopic and vaginal hysterectomy: analysis of a large United States payer measuring quality and cost of care.
      ,
      • Spilsbury K.
      • Semmens J.B.
      • Hammond I.
      • Bolck A.
      Persistent high rates of hysterectomy in Western Australia: a population-based study of 83 000 procedures over 23 years.
      ,
      • Sowers M.
      • Tomey K.
      • Jannausch M.
      • Eyvazzadeh A.
      • Nan B.
      • Randolph Jr., J.
      Physical functioning and menopause states.
      ]. Some studies have shown that hysterectomy was associated with increased long-term coronary heart disease and hypertension [
      • Choi H.G.
      • Koh Y.S.
      • Lee S.W.
      Increased risk of coronary heart disease with hysterectomy in young women: a longitudinal follow-up study using a national health screening cohort.
      ,
      • Madika A.L.
      • MacDonald C.J.
      • Gelot A.
      • Hitier S.
      • Mounier-Vehier C.
      • Béraud G.
      • Kvaskoff M.
      • Boutron-Ruault M.C.
      • Bonnet F.
      Hysterectomy, non-malignant gynecological diseases, and the risk of incident hypertension: the E3N prospective cohort.
      ]. Depressive symptoms after hysterectomy have been extensively studied; however, the results reported were inconsistent between studies. For instance, a postoperative cohort study that included 53 women who had undergone hysterectomy reported no association with depressive symptoms at three months after the surgery [
      • Bahri N.
      • Tohidinik H.R.
      • Najafi T.Fathi
      • Larki M.
      • Amini T.
      • Sartavosi Z.Askari
      Depression following hysterectomy and the influencing factors.
      ]. Moreover, some authors reported that women who underwent hysterectomy had a better quality of life and a reduced fear of cancer [
      • Rannestad T.
      Hysterectomy: effects on quality of life and psychological aspects.
      ]. A prospective multicenter cohort study with 419 women who underwent hysterectomy reported that women experiencing depression before hysterectomy for benign indication were observed to have remarkable improvements on postoperative depression after a year of follow-up [
      • Theunissen M.
      • Peters M.L.
      • Schepers J.
      • Schoot D.C.
      • Gramke H.F.
      • Marcus M.A.
      Prevalence and predictors of depression and well-being after hysterectomy: an observational study.
      ]. It should be noted that these studies had relatively short follow-up periods.
      Previous longitudinal research found that hysterectomy posed a higher risk for depressive symptoms in women after surgery [
      • Chou P.H.
      • Lin C.H.
      • Cheng C.
      • Chang C.L.
      • Tsai C.J.
      • Tsai C.P.
      • Lan T.H.
      • Chan C.H.
      Risk of depressive disorders in women undergoing hysterectomy: a population-based follow-up study.
      ,
      • Laughlin-Tommaso S.K.
      • Satish A.
      • Khan Z.
      • Smith C.Y.
      • Rocca W.A.
      • Stewart E.A.
      Long-term risk of de novo mental health conditions after hysterectomy with ovarian conservation: a cohort study.
      ,
      • Wilson L.
      • Pandeya N.
      • Byles J.
      • Mishra G.
      Hysterectomy and incidence of depressive symptoms in midlife women: the Australian longitudinal study on women's health.
      ]. Although the risk of depressive symptoms after hysterectomy has been confirmed in long-term follow-up studies, there has been no literature examining the use of antidepressant therapy among women who had undergone hysterectomy. In addition, a few studies suggested that non-Hispanic black women and women from other racial-ethnic groups were less likely to be diagnosed depression or receive psychotropic medications compared with non-Hispanic white women [
      • Barnes D.M.
      • Bates L.M.
      Do racial patterns in psychological distress shed light on the black-white depression paradox?A systematic review.
      ,
      • Coleman K.J.
      • Stewart C.
      • Waitzfelder B.E.
      • Zeber J.E.
      • Morales L.S.
      • Ahmed A.T.
      • Ahmedani B.K.
      • Beck A.
      • Copeland L.A.
      • Cummings J.R.
      • Hunkeler E.M.
      • Lindberg N.M.
      • Lynch F.
      • Lu C.Y.
      • Owen-Smith A.A.
      • Trinacty C.M.
      • Whitebird R.R.
      • Simon G.E.
      Racial-ethnic differences in psychiatric diagnoses and treatment across 11 health care systems in the mental health research network.
      ]; however, none of these studies focused on the association of race and use of antidepressants after hysterectomy.
      Thus, the purpose of this study was to explore whether there is an association between hysterectomy and the use of antidepressants, stratified by bilateral oophorectomy status, among women of different races. We used a nationally representative sample obtained from the National Health and Nutrition Examination Survey (NHANES).

      2. Materials and methods

      2.1 Study population

      The study data were obtained from NHANES (https://www.cdc.gov/nchs/nhanes/index.htm). The NHANES database was designed to assess the health and nutritional status of adults and children in the United States. It is a nationally representative, cross-sectional survey conducted by the U.S. National Center for Health Statistics. Since 1999, a series of large, stratified, multistage probability sampling processes were used to select about 5000 persons every year across the nation to complete the survey; each survey cycle lasts for two years [
      • Ahluwalia N.
      • Dwyer J.
      • Terry A.
      • Moshfegh A.
      • Johnson C.
      Update on NHANES dietary data: focus on collection, release, analytical considerations, and uses to inform public policy.
      ]. The contents of the survey include demographic, socioeconomic, dietary, and health-related questions, and the questionnaires consist of questions regarding medical, dental, and physiological health [
      • Fain J.A.
      NHANES.
      ].
      Data from two cycles of NHANES (2015–2016 and 2017–2018) were used in this study. Among the 23,181 participants, 9776 were females. We further excluded women without information on the use of medication for depression (n = 3720) or those without information on their history of hysterectomy (n = 1098), we also excluded women who underwent oophorectomy without hysterectomy (n = 70). Finally, data from a total of 4888 women between the ages of 20 and 80 years old were analyzed. The Institutional Review Board of NCHS had approved each survey, and each participant provided a written informed consent.

      2.2 Major variable assessment

      The use of antidepressants was the dependent variable (outcome). Information on antidepressant usage was obtained from the participants' self-reported responses to the following question from the Disability Questionnaire (DLQ): “Do you take medication for depression?” History of hysterectomy was the independent variable. Information about history of hysterectomy and oophorectomy were extracted from the following two questions in reproductive health section of the questionnaire: “Have you had a hysterectomy that is, surgery to remove your uterus or womb?” and “Have you had both of your ovaries removed either when you had your uterus removed or at another time?” We organized the responses to history of hysterectomy into three groups: never had hysterectomy, undergone hysterectomy without oophorectomy, and undergone hysterectomy with oophorectomy.

      2.3 Covariates

      According to previous reports and availability of records in the NHANES [
      • Shen Y.
      • Varma D.S.
      • Zheng Y.
      • Boc J.
      • Hu H.
      Age at menarche and depression: results from the NHANES 2005–2016.
      ,
      • Barsha R.A.A.
      • Hossain M.B.
      Trouble sleeping and depression among US women aged 20 to 30 years.
      ], the following variables are considered to be possible confounders: (a) demographic characteristics including age (20–80 years old, as a continuous variable), race (non-Hispanic white, non-Hispanic black, Mexican American, and others, including Hispanic, Asian and multi-racial), education (less than high school, high school graduate, more than high school, or missing), marital status (married/living with partner, not married, widowed/divorced/separated, or missing), occupation (employed, unemployed, or missing), (b) socioeconomic status as measured by poverty income ratio (<1.0, 1.0–2.0, >2.0, or missing), (c) alcohol use (≥4 drinks every day, <4 drinks every day, or missing), (d) smoking status (current smoker, former smoker, non-smoker, or missing), (e) body mass index (BMI) (<18.5, 18.5–25.0, 25.0–30.0, 30.0–35.0, ≥35.0, or missing), (f) use of female hormones, ever (hormone replacement therapy) (yes, no, or missing), (g) regular periods in the past year (regular period, undergone hysterectomy, natural menopause), (h) hours of sleep (average number of sleeping hours per day), and (i) current depression; the 9-item Patient Health Questionnaire (PHQ-9) was used to evaluate current symptoms of depression. Poverty income ratio measures the ratio of family income to poverty thresholds at the household level. The poverty income ratio adjusts for household size and geographic region, with lower values equating to higher poverty levels. The score of the PHQ-9 was treated as a covariate for the analysis.

      2.4 Statistical analysis

      The complex sampling design followed the U.S. National Center for Health Statistics guidelines, and sampling weights were calculated based on the analytical guideline [
      • Fain J.A.
      NHANES.
      ]. All analyses were calculated using the R statistical package version 3.4.3 (http://www.R-project.org) and EmpowerStats software (http://www.empowerstats.com). Multivariable logistic regression models were used to estimate the associations of hysterectomy with use of antidepressants. Two models were established: Model 1, with no covariates controlled; and Model 2, with all the covariates controlled. Subgroup analyses by races were also conducted.
      This was a type II prognostic study which investigates the relationship between hysterectomy and the use of antidepressants. The sample size calculation required 10 events for each variable in the multivariable logistic regression model [
      • Yao X.
      • Vella E.
      • Brouwers M.
      How to conduct a high-quality original study on a prognostic research topic.
      ,
      • Yao X.
      • Florez I.D.
      • Zhang P.
      • Zhang C.
      • Zhang Y.
      • Wang C.
      • Liu X.
      • Nie X.
      • Wei B.
      • Ghert M.A.
      Clinical research methods for treatment, diagnosis, prognosis, etiology, screening, and prevention: a narrative review.
      ]. In Model 2, we planned to include 14 independent variables; therefore, a minimum of 140 participants reporting use of antidepressants were required. An odds ratio (OR) with 95 % confidence intervals (CIs) was calculated as a measure of association between the independent variable and the outcome (dependent variable). For continuous variables, mean ± standard deviation (SD) was presented, and the p-value was calculated by weighted linear regression model. For categorical variables, the percentage was presented, and the p-value was calculated by weighted chi-square test. The significance level was set at 0.05 (p < 0.05). Multiple imputation based on replications and chained equation approach method in the R MI procedure was used to account for missing data. Regression analysis was conducted on the five sets of data and the OR values and 95 % confidence intervals of the five regression models were merged [
      • Su Y.S.
      • Gelman A.
      • Hill J.
      • Yajima M.
      Multiple imputation with diagnostics (mi) in R: opening windows into the black box.
      ]. The STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) statement guideline was followed.

      3. Results

      The flow chart of history of hysterectomy after ethnic stratification was shown in Fig. 1. Among the 4888 participants, the average age of 1052 women at the time of hysterectomy was 41.49 years old (range: 19–60). Among them, the average age of 564 women at the time of both hysterectomy and oophorectomy was 43.69 years old (range: 19–60). There were 632 participants taking antidepressants and Table 1 provided the characteristics of our study population, stratified by use of antidepressants. The women taking antidepressants were older (54.03 ± 15.65 vs 49.46 ± 17.64 years; p < 0.001) and were more likely to be unemployed (65.19 % vs 43.94 %; p < 0.001) than those who were not taking antidepressants. Non-Hispanic white women, those who were widowed/divorced/separated, those who had undergone hysterectomy only or both hysterectomy and oophorectomy, those who used female hormones, and who did not have regular periods in the past year due to hysterectomy were more likely to take antidepressants (p < 0.001). Women taking antidepressants were more likely to be current smokers (21.99 % vs 10.71 %; p < 0.001), drink four or more alcoholic drinks every day (15.51 % vs 5.78 %; p < 0.001), have BMI ≥ 35.0 (32.59 % vs 22.25 %; p < 0.001), live below the federal poverty level < 1.0 (25.16 % vs 18.70 %; p < 0.001), score higher on PHQ-9 (7.97 ± 5.92 vs 3.05 ± 3.90; p < 0.001), and experience more sleeping problems (69.15 % vs 25.80 %; p < 0.001) than those who were not taking antidepressants.
      Fig. 1
      Fig. 1Flow chart of history of hysterectomy after ethnic stratification.
      NH: never had hysterectomy; H: undergone hysterectomy without oophorectomy; HO: undergone hysterectomy with oophorectomy.
      Table 1Characteristics of study sample in NHANES 2015–2018, stratified by use of antidepressants.
      VariableTaking antidepressants

      n (%) or mean ± SD
      Not Taking antidepressants

      n (%) or mean ± SD
      p-Value
      Total number of participants6324256
      Age, years54.03 ± 15.6549.46 ± 17.64<0.001
      Chi-square test. Significance at p < 0.05.
      Race<0.001
      Chi-square test. Significance at p < 0.05.
       Non-Hispanic white315 (49.84)1335 (31.37)
       Non-Hispanic black116 (18.35)982 (23.07)
       Mexican American75 (11.87)712 (16.73)
       Other races
      Other races included Hispanic, Asian, and multi-racial.
      126 (19.94)1227 (28.83)
      Education0.059
       <High school145 (22.98)801 (18.83)
       High school123 (19.49)945 (22.22)
       >High school363 (57.53)2507 (58.95)
       Missing1 (0.16)3 (0.07)
      Marital status<0.001
      Chi-square test. Significance at p < 0.05.
       Married/living with partner119 (18.83)760 (17.86)
       Never married231 (36.55)1991 (46.78)
       Widowed/divorced/separated282 (44.62)1503 (35.31)
       Missing0 (0.00)2 (0.05)
      Occupation<0.001
      Chi-square test. Significance at p < 0.05.
       Employed219 (34.65)2381 (55.94)
       Unemployed412 (65.19)1870 (43.94)
       Missing1 (0.16)5 (0.12)
      Percentage of federal poverty level<0.001
      Chi-square test. Significance at p < 0.05.
       <1.0159 (25.16)796 (18.70)
       1.0–2.0164 (25.95)1020 (23.97)
       >2.0237 (37.50)1960 (46.05)
       Missing72 (11.39)480 (11.28)
      Smoking status<0.001
      Chi-square test. Significance at p < 0.05.
       Current smoker139 (21.99)456 (10.71)
       Former smoker29 (4.59)119 (2.80)
       Non-smoker156 (24.68)693 (16.28)
       Missing308 (48.73)2988 (70.21)
      Alcohol use<0.001
      Chi-square test. Significance at p < 0.05.
       ≥4 drinks every day98 (15.51)246 (5.78)
       <4 drinks every day452 (71.52)3162 (74.30)
       Missing82 (12.97)848 (19.92)
      History of hysterectomy<0.001
      Chi-square test. Significance at p < 0.05.
       Never had hysterectomy397 (62.82)3439 (80.80)
       Undergone hysterectomy without oophorectomy99 (15.66)396 (9.30)
       Undergone hysterectomy with oophorectomy136 (21.52)421 (9.89)
      Use of female hormones ever<0.001
      Chi-square test. Significance at p < 0.05.
       Yes155 (24.53)623 (14.66)
       No475 (75.16)3613 (85.03)
       Missing2 (0.32)13 (0.31)
      Regular periods in the past year
      These variables do not have any missing values.
      <0.001
      Chi-square test. Significance at p < 0.05.
       Regular periods193 (30.54)2021 (47.49)
       Undergone hysterectomy235 (37.18)817 (19.20)
       Natural menopause204 (32.28)1418 (33.32)
      BMI<0.001
      Chi-square test. Significance at p < 0.05.
       <18.56 (0.95)72 (1.69)
       18.5–25.0111 (17.56)1123 (26.39)
       25.0–30.0141 (22.31)1197 (28.12)
       30.0–35.0162 (25.63)883 (20.75)
       ≥35.0206 (32.59)947 (22.25)
       Missing6 (0.95)34 (0.80)
      Sleeping problems<0.001
      Chi-square test. Significance at p < 0.05.
       Yes437 (69.15)1098 (25.80)
       No193 (30.54)3157 (74.18)
       Missing2 (0.32)1 (0.02)
      Hours of sleep
      These variables do not have any missing values.
      8.20 ± 1.787.70 ± 1.53<0.001
      Chi-square test. Significance at p < 0.05.
      Current depression score
      These variables do not have any missing values.
      7.97 ± 5.923.05 ± 3.90<0.001
      Chi-square test. Significance at p < 0.05.
      BMI: body mass index; SD: standard deviation.
      low asterisk Chi-square test. Significance at p < 0.05.
      a Other races included Hispanic, Asian, and multi-racial.
      b These variables do not have any missing values.
      The results of the logistic regression models are presented in Table 2 (n = 4888). A positive association between hysterectomy without oophorectomy and the use of antidepressants was found in the Model 2 (OR = 2.13, 95 % CI = 1.43–3.17, p = 0.000) after adjusting for potential covariates. The association between hysterectomy with oophorectomy and use of antidepressants was also positive in Model 2 (OR = 2.04, 95 % CI = 1.35–3.06, p = 0.001).
      Table 2The associations between hysterectomy (without or with oophorectomy) and use of antidepressants.
      ExposureModel 1 OR (95 % CI)p-ValueModel 2
      Age, other races, educational level, marital status, occupation, ratio of family income to poverty, smoking status, alcohol use, use of female hormones ever, regular periods in the past year, body mass index, sleeping trouble, sleep hours, depression were adjusted in Model 2.
      OR (95 % CI)
      p-Value
      Never had HReferenceReference
      Undergone H without O2.17 (1.70, 2.76)<0.000
      Chi-square test. Significance at p < 0.05.
      2.13 (1.43, 3.17)0.000
      Chi-square test. Significance at p < 0.05.
      Undergone H with O2.80 (2.25, 3.49)<0.000
      Chi-square test. Significance at p < 0.05.
      2.04 (1.35, 3.06)0.001
      Chi-square test. Significance at p < 0.05.
      Non-Hispanic white
       Never had HReferenceReference
       Undergone H without O2.08 (1.44, 3.00)0.000
      Chi-square test. Significance at p < 0.05.
      1.89 (1.04, 3.44)0.038
      Chi-square test. Significance at p < 0.05.
       Undergone H with O2.31 (1.70, 3.13)<0.000
      Chi-square test. Significance at p < 0.05.
      1.78 (1.00, 3.24)0.050
      Non-Hispanic black
       Never had HReferenceReference
       Undergone H without O1.13 (0.64, 2.00)0.6681.90 (0.75, 4.82)0.174
       Undergone H with O1.96 (1.15, 3.35)0.014
      Chi-square test. Significance at p < 0.05.
      3.09 (1.15, 8.27)0.024
      Chi-square test. Significance at p < 0.05.
      Mexican American
       Never had HReferenceReference
       Undergone H without O2.58 (1.27, 5.26)0.009
      Chi-square test. Significance at p < 0.05.
      1.75 (0.53, 5.76)0.360
       Undergone H with O3.05 (1.56, 5.97)0.001
      Chi-square test. Significance at p < 0.05.
      2.28 (0.65, 7.94)0.196
      Other races
      Other races included Hispanic, Asian, and multi-racial.
       Never had HReferenceReference
       Undergone H without O3.73 (2.25, 6.19)<0.000
      Chi-square test. Significance at p < 0.05.
      3.14 (1.30, 7.56)0.010
      Chi-square test. Significance at p < 0.05.
       Undergone H with O3.62 (2.16, 6.05)<0.000
      Chi-square test. Significance at p < 0.05.
      1.93 (0.81, 4.56)0.136
      H, hysterectomy; O, oophorectomy; OR, odds ratio; CI, confidence interval.
      low asterisk Chi-square test. Significance at p < 0.05.
      a Age, other races, educational level, marital status, occupation, ratio of family income to poverty, smoking status, alcohol use, use of female hormones ever, regular periods in the past year, body mass index, sleeping trouble, sleep hours, depression were adjusted in Model 2.
      b Other races included Hispanic, Asian, and multi-racial.
      After stratifying by race, a positive association between hysterectomy without oophorectomy and the use of antidepressants were reported in 1650 non-Hispanic white women (Model 1: n = 48 taking antidepressant; OR = 2.08, 95 % CI = 1.44–3.00, p < 0.000; Model 2: n = 48 taking antidepressant; OR = 1.89, 95 % CI = 1.04–3.44, p = 0.038), and 1353 women of other races (Model 1: n = 24 taking antidepressant; OR = 3.73, 95 % CI = 2.25–6.19, p < 0.000; Model 2: n = 24 taking antidepressant; OR = 3.14, 95 % CI = 1.30–7.56, p = 0.010). Also, the positive association between hysterectomy with oophorectomy and use of antidepressants was only reported in 1098 non-Hispanic black women (Model 1: n = 20 taking antidepressant; OR = 1.96, 95 % CI = 1.15–3.35, p = 0.014; Model 2: n = 20 taking antidepressant; OR = 3.09, 95 % CI = 1.15–8.27, p = 0.024) (Table 2), it is worth noting that the estimate of 95 % CI interval has increased after adjustment, so it is likely the result of confounding. No significant association was found in non-Hispanic black and Mexican American women who had undergone hysterectomy without oophorectomy, and no significant association was found in non-Hispanic white, Mexican American women and women of other races who had undergone hysterectomy with oophorectomy.

      4. Discussion

      This study suggested that hysterectomy was significantly associated with use of antidepressants. Those associations were found in non-Hispanic white women and women of other races (including Hispanic, Asian, and Multi-Racial races) who had undergone hysterectomy without oophorectomy. Associations were not found in non-Hispanic black and Mexican American women who had undergone hysterectomy only, and associations were not found in non-Hispanic white, Mexican American women and women of other races who had undergone hysterectomy with oophorectomy.
      In this study, the average age of participants at time of hysterectomy was 41.49 years old, while the average age of participants at time of survey was 54.03 years old, which suggested that it may take a long time for depressive symptoms to appear after undergoing hysterectomy with or without oophorectomy. This result was consistent with some existing longitudinal studies. A 12-year follow-up study showed that women who had undergone hysterectomy with or without oophorectomy had a higher risk of experiencing depressive symptoms (RR = 1.20; 95 % CI = 1.06–1.36 and RR = 1.44; 95 % CI = 1.22–1.68, respectively) after more than five years after hysterectomy than those who did not undergo hysterectomy [
      • Wilson L.
      • Pandeya N.
      • Byles J.
      • Mishra G.
      Hysterectomy and incidence of depressive symptoms in midlife women: the Australian longitudinal study on women's health.
      ]. A 5-year follow-up study that included women who had undergone hysterectomy with ovarian conservation reported that women who had undergone hysterectomy were at a greater risk of depression compared with women who had not undergone hysterectomy (HR = 1.78; 95 % CI = 1.46–2.18) [
      • Chou P.H.
      • Lin C.H.
      • Cheng C.
      • Chang C.L.
      • Tsai C.J.
      • Tsai C.P.
      • Lan T.H.
      • Chan C.H.
      Risk of depressive disorders in women undergoing hysterectomy: a population-based follow-up study.
      ]. Furthermore, among younger women between the ages of 18 to 35 years, the risk of depression at 15 years after surgery was higher among those who had undergone hysterectomy compared with those who had undergone hysterectomy with ovarian conservation [
      • Laughlin-Tommaso S.K.
      • Satish A.
      • Khan Z.
      • Smith C.Y.
      • Rocca W.A.
      • Stewart E.A.
      Long-term risk of de novo mental health conditions after hysterectomy with ovarian conservation: a cohort study.
      ].
      Some studies strongly supported that hysterectomy increased the risk of earlier ovarian failure, due to low estrogen levels after surgery [
      • Chang S.H.
      • Kim C.S.
      • Lee K.S.
      • Kim H.
      • Yim S.V.
      • Lim Y.J.
      • Park S.K.
      Premenopausal factors influencing premature ovarian failure and early menopause.
      ]. In a study, 60 of 406 (14.8 %) premenopausal women experienced ovarian failure in a four-year follow-up after hysterectomy without bilateral oophorectomy, while only 37 of 465 (8.0 %) women who did not undergo hysterectomy had an ovarian failure [
      • Moorman P.G.
      • Myers E.R.
      • Schildkraut J.M.
      • Iversen E.S.
      • Wang F.
      • Warren N.
      Effect of hysterectomy with ovarian preservation on ovarian function.
      ]. In a 5-year follow-up study, among the 257 women who had undergone hysterectomy, 53 (20.6 %) reached menopause (defined by as a single Follicle Stimulating Hormone (FSH) measurement of at least 40 IU/L) compared to 19 (7.3 %) of 259 women who did not undergo hysterectomy [
      • Farquhar C.M.
      • Sadler L.
      • Harvey S.A.
      • Stewart A.W.
      The association of hysterectomy and menopause: a prospective cohort study.
      ]. Thus, the low estrogen concentrations may have driven the onset of menopause. Furthermore, previous studies suggested estrogen deficiency may play an important role in the onset of climacteric depression [
      • Studd J.
      • Nappi R.E.
      Reproductive depression.
      ,
      • Sarrel P.M.
      • Sullivan S.D.
      • Nelson L.M.
      Hormone replacement therapy in young women with surgical primary ovarian insufficiency.
      ]. To prevent post-hysterectomy depression, regular endocrinological monitoring has been recommended to surveil ovarian failure after hysterectomy [
      • Khastgir G.
      • Studd J.
      Patients' outlook, experience, and satisfaction with hysterectomy, bilateral oophorectomy, and subsequent continuation of hormone replacement therapy.
      ].
      Due to the high prevalence of depressive symptoms after hysterectomy, patients who experience depressive symptoms should be referred to psychiatric care. Failure to discover and treat depression may result in worse health outcomes and heavier financial burden, and patients experiencing depressive symptoms may be prone to comorbid drug use and may even attempt to commit suicide [
      • Carey E.T.
      • Moore K.J.
      • Young J.C.
      • Bhattacharya M.
      • Schiff L.D.
      • Louie M.Y.
      • Park J.
      • Strassle P.D.
      Association of preoperative depression and anxiety with long-term opioid use after hysterectomy for benign indications.
      ]. However, at present, there is a lack of information about specific treatments for depressive symptoms experienced after hysterectomy. In this study, we found a significant association between antidepressants use and the hysterectomy among middle-aged women in America, which indicated that further research regarding the specific treatments for depressive symptoms experienced after hysterectomy is necessary.
      A large number of studies elucidated numerous and varied depressive symptoms among women during perimenopause. Depressive symptoms, except for depressive mood, were also related with common somatic symptoms found among middle-aged women, including sleep problems, dizziness, headaches, asthenia, muscle pain, and urinary incontinence [
      • Freeman E.W.
      • Sammel M.D.
      • Lin H.
      • Gracia C.R.
      • Kapoor S.
      Symptoms in the menopausal transition: hormone and behavioral correlates.
      ,
      • Terauchi M.
      • Hiramitsu S.
      • Akiyoshi M.
      • Owa Y.
      • Kato K.
      • Obayashi S.
      • Matsushima E.
      • Kubota T.
      Associations among depression, anxiety and somatic symptoms in peri- and postmenopausal women.
      ,
      • Wang H.L.
      • Booth-LaForce C.
      • Tang S.M.
      • Wu W.R.
      • Chen C.H.
      Depressive symptoms in taiwanese women during the peri- and post-menopause years: associations with demographic, health, and psychosocial characteristics.
      ,
      • Waetjen L.E.
      • Liao S.
      • Johnson W.O.
      • Sampselle C.M.
      • Sternfield B.
      • Harlow S.D.
      • Gold E.B.
      Factors associated with prevalent and incident urinary incontinence in a cohort of midlife women: a longitudinal analysis of data: study of women's health across the nation.
      ]. It was difficult to identify whether the cause of these symptoms was a result of depression or physical decline [
      • Ormel J.
      • Rijsdijk F.V.
      • Sullivan M.
      • van Sonderen E.
      • Kempen G.I.
      Temporal and reciprocal relationship between IADL/ADL disability and depressive symptoms in late life.
      ]. Some studies suggested that menopausal women who experienced major depression (excluding bipolar disorder) and required psychiatric treatment (such as psychological interventions and antidepressant therapy), and displayed moderate or above depressive symptoms should be treated with antidepressants [
      • Bromberger J.T.
      • Epperson C.N.
      Depression during and after the perimenopause: impact of hormones, genetics, and environmental determinants of disease.
      ]. Furthermore, there has been a focus on the therapeutic effects of antidepressants on depressive symptoms in middle-aged women. Two randomized, double-blind, placebo-controlled trials reported that desvenlafaxine, when compared with placebo, significantly improved the depressive symptoms of major depressive disorder in perimenopausal and postmenopausal women [
      • Kornstein S.G.
      • Jiang Q.
      • Reddy S.
      • Musgnung J.J.
      • Guico-Pabia C.J.
      Short-term efficacy and safety of desvenlafaxine in a randomized, placebo-controlled study of perimenopausal and postmenopausal women with major depressive disorder.
      ,
      • Liebowitz M.R.
      • Tourian K.A.
      Efficacy, safety, and tolerability of desvenlafaxine 50 mg/d for the treatment of major depressive disorder:a systematic review of clinical trials.
      ]. In some small open-label studies, some selective serotonin reuptake inhibitors (including citalopram, escitalopram and vortioxetine), serotonin-norepinephrine reuptake inhibitors (including venlafaxine and duloxetine) and mirtazapine had shown favorable effects on mood and somatic symptoms (such as vasomotor symptoms, insomnia, and pain) [
      • Soares C.N.
      • Poitras J.R.
      • Prouty J.
      • Alexander A.B.
      • Shifren J.L.
      • Cohen L.S.
      Efficacy of citalopram as a monotherapy or as an adjunctive treatment to estrogen therapy for perimenopausal and postmenopausal women with depression and vasomotor symptoms.
      ,
      • Soares C.N.
      • Arsenio H.
      • Joffe H.
      • Bankier B.
      • Cassano P.
      • Petrillo L.F.
      • Cohen L.S.
      Escitalopram versus ethinyl estradiol and norethindrone acetate for symptomatic peri- and postmenopausal women: impact on depression, vasomotor symptoms, sleep, and quality of life.
      ,
      • Joffe H.
      • Soares C.N.
      • Petrillo L.F.
      • Viguera A.C.
      • Somley B.L.
      • Koch J.K.
      • Cohen L.S.
      Treatment of depression and menopause-related symptoms with the serotonin-norepinephrine reuptake inhibitor duloxetine.
      ,
      • Joffe H.
      • Groninger H.
      • Soares C.N.
      • Nonacs R.
      • Cohen L.S.
      An open trial of mirtazapine in menopausal women with depression unresponsive to estrogen replacement therapy.
      ].
      Due to estrogen withdrawal, women during the menopause transition are vulnerable to depressed mood [
      • Genazzani A.R.
      • Spinetti A.
      • Gallo R.
      • Bernardi F.
      Menopause and the central nervous system: intervention options.
      ]. Some studies have reported that menopausal hormone therapy (MHT) may accelerate the response of selective serotonin reuptake inhibitors, and improve the rates of partial remission [
      • Thase M.E.
      • Entsuah R.
      • Cantillon M.
      • Kornstein S.G.
      Relative antidepressant efficacy of venlafaxine and SSRIs: sex-age interactions.
      ,
      • Zanardi R.
      • Rossini D.
      • Magri L.
      • Malaguti A.
      • Colombo C.
      • Smeraldi E.
      Response to SSRIs and role of the hormonal therapy in post-menopausal depression.
      ]. However, MHT is not approved for the treatment of depression in either Europe or USA due to insufficient evidence. In the current study, “use of female hormones, ever” were used more among women who also use antidepressants than those who do not use antidepressant. Thus, we adjusted the variable of “use of female hormones, ever” in Model 2, and did not find this variable to modify the relationship between hysterectomy status and the use of antidepressants.
      In addition, studies have shown that some women may feel a sense of loss, as the removal of the uterus can also be seen as a loss of femininity [
      • Yen J.Y.
      • Chen Y.H.
      • Long C.Y.
      • Chang Y.
      • Yen C.F.
      • Chen C.C.
      • Ko C.H.
      Risk factors for major depressive disorder and the psychological impact of hysterectomy: a prospective investigation.
      ]. Some thought that the surgery may have affected the individual's identity as a female as they can no longer child bear after hysterectomy [
      • Rannestad T.
      Hysterectomy: effects on quality of life and psychological aspects.
      ]. These psychological factors may also contribute to post-hysterectomy depression. A study had shown that education and cognitive interventions were effective in reducing postoperative anxiety in Chinese women who have undergone hysterectomy [
      • Cheung L.H.
      • Callaghan P.
      • Chang A.M.
      A controlled trial of psycho-educational interventions in preparing Chinese women for elective hysterectomy.
      ].
      Additionally, our study found different associations between antidepressants use and hysterectomy among women from different races. Compared with non-Hispanic white women, fewer Mexican American women who had undergone hysterectomy with or without oophorectomy received antidepressant treatment. The racial/ethnic disparities in depression symptoms among women who have undergone hysterectomy were seldomly reported, and there are knowledge gaps in understanding mental health conditions among different races [
      • Chiuve S.E.
      • Huisingh C.
      • Petruski-Ivleva N.
      • Owens C.
      • Kuohung W.
      • Wise L.A.
      Uterine fibroids and incidence of depression, anxiety and self-directed violence: a cohort study.
      ]. Financial difficulties were related to mental health status - older African-American adults were less likely than their white counterparts to receive antidepressants [
      • Evans M.C.
      • Bazargan M.
      • Cobb S.
      • Assari S.
      Mental and physical health correlates of financial difficulties among African-American older adults in low-income areas of Los Angeles.
      ,
      • Cobb S.
      • Bazargan M.
      • Sandoval J.C.
      • Wisseh C.
      • Evans M.C.
      • Assari S.
      Depression treatment status of economically disadvantaged african american older adults.
      ]. Another study reported that half of the non-English-speaking women were less likely to receive adequate antidepressants due to the poor communication and language barrier [
      • Keller A.O.
      • Gangnon R.
      • Witt W.P.
      The impact of patient-provider communication and language spoken on adequacy of depression treatment for U.S. women.
      ]. However, it should be noted that after ethnic stratification, the risk of antidepressant use was increased in all groups after hysterectomy, and there was an overlap of 95 % confidence intervals between groups. In addition, because the number of women who had undergone hysterectomy and were taking antidepressants in each race group was small after ethnic stratification, the upper limit of the confidence interval may be rather large. Further studies focusing on effect of antidepressant treatment among different races with appropriate sample sizes are required.
      Some authors reported that hysterectomy after the age of 45 years was related with weight gain and sleeping problems after the surgery [
      • Guthrie J.R.
      • Clark M.S.
      • Dennerstein L.
      A prospective study of outcomes after hysterectomy in mid-aged Australian-born women.
      ], therefore, we stratified by the age at hysterectomy in our analysis. However, we did not find a statistically significant difference between the age groups, which may be a result of our small sample size of women who had undergone hysterectomy. This topic should be further explored in future research. In this study, we had conducted analyses using current depression as the outcome variable, but we did not find an association between hysterectomy and depression. There are two possible reasons for this finding. First, the antidepressants may have been alleviating symptoms among these patients and therefore they were not reporting severe symptoms in the PHQ-9. Second, current depression is measured by PHQ-9 in NHANES, which is a self-administered questionnaire and may not accurately diagnose depression [
      • Kroenke K.
      PHQ-9: global uptake of a depression scale.
      ]. A patient with depression diagnosed by a psychiatrist may have a very low PHQ-9 score.
      Several strengths exist in this study. First, this study was the first to evaluate the association between antidepressants use and hysterectomy using the US national sample. Second, the participants who had undergone hysterectomy in this study were divided into those with or without oophorectomy; thus, eliminating the bias caused by the different underlying characteristic of the enrolled patients. In addition, this was the first study to analyze the use of antidepressants among women of different races who had undergone hysterectomy with or without oophorectomy. There are also several limitations in this study. First, this is a cross-sectional study, so the result could only reflect an association between dependent and independent variables. It is unable to observe a patient both prior to and after their hysterectomy as this is not a longitudinal cohort study. Second, estrogen level is an important influencing factor in depressive symptoms in women. However, due to a lack of information on the participants' estrogen levels, we were unable to include estrogen level information into the model. Third, the types and duration of hormone therapy were not included in the analysis due to the large amount of missing data in these variables. Fourth, the data on using antidepressants and the information on hysterectomy and oophorectomy were both obtained via self-report, which may be prone to recall bias. Fifth, the NHANES database did not provide any data on vasomotor symptoms and the indication for the surgery. This is important to note as they may play a differential role in antidepressant use. Finally, each type of antidepressant works differently and some may be better in improving certain symptoms than others; however, there was no information on specific antidepressants in NHANES, therefore, subgroup analyses for different antidepressants cannot be performed.

      5. Conclusion

      In summary, this study found that hysterectomy was positively and significantly associated with antidepressant use in the US. This was the first study to provide information on antidepressant treatment after hysterectomy, although there was no information on the use of specific antidepressants. These results may differ by race. Future studies should focus on psychosocial and medical interventions for women post-hysterectomy.

      Contributors

      L. J. Li contributed to conceptualization and performing formal analysis, and was responsible for writing the original draft.
      Q. Chen contributed to conceptualization.
      N. Zhang contributed to conceptualization and methodology.
      X. Yao contributed to conceptualization, methodology, and interpretation of data.
      C. X. Wang contributed to conceptualization, interpretation of data, and supervision.
      All authors contributed to and approved the final manuscript.

      Funding

      This work was supported by the National Key Research and Development Program of China (No. 2020YFC2005304 ), Beijing Key Clinical Specialty, Capital's Funds for Health Improvement and Research (No. 2020-2-2044 ).

      Ethical approval

      The ethics review board of the National Center for Health Statistics approved all NHANES protocols and written informed consents were obtained from all participants.

      Provenance and peer review

      This article was not commissioned and was externally peer reviewed.

      Research data (data sharing and collaboration)

      There are no linked research data sets in this paper. The data are available from NHANES.

      Declaration of competing interest

      The authors report no competing interest for this work.

      Acknowledgements

      The authors thank Kristy Yiu for proofreading the article.

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