Gynecologic Oncology 113 (2009) 128–133

Contents lists available at ScienceDirect

Gynecologic Oncology

j ourna l homepage: www.e lsev ie r.com/ locate /ygyno

A controlled study of mental distress and somatic complaints after risk-reducingsalpingo-oophorectomy in women at risk for hereditary breast ovarian cancer

Trond M. Michelsen a,b,c,⁎, Anne Dørum c,d, Alv A. Dahl c,e

a Department of Gynecology, Sørlandet Hospital Arendal, Sykehusveien 1, Servicebox 605, N-4809 Arendal, Norwayb National Resource Centre for Women's Health, Rikshospitalet University Hospital, 0027 Oslo, Norwayc Faculty Division The Norwegian Radium Hospital, University of Oslo, 0316 Oslo, Norwayd Section of Gynecological Oncology, The Norwegian Radium Hospital, Rikshospitalet University Hospital, 0310 Oslo, Norwaye Department of Clinical Cancer Research, The Norwegian Radium Hospital, Rikshospitalet University Hospital, 0310 Oslo, Norway

⁎ Corresponding author. Department of GynecologySykehusveien 1, Servicebox 605, N-4809 Arendal, Norw

E-mail address: trond.melbye.michelsen@sshf.no (T.

0090-8258/$ – see front matter © 2009 Elsevier Inc. Adoi:10.1016/j.ygyno.2008.12.024

a b s t r a c t

a r t i c l e i n f o

Article history:

Objectives. Risk-reducing Received 22 October 2008Available online 29 January 2009

Keywords:Genes, BRCA1Genes, BRCA2Genetic predisposition to diseaseOophorectomyAnxiety disordersDepressive disorder

salpingo-oophorectomy (RRSO) provides effective protection against ovariancancer in BRCA mutation carriers and in women at risk for hereditary breast ovarian cancer, but little isknown about non-oncologic morbidity after the procedure. We explored mental distress and somaticcomplaints in women after RRSO compared to controls from the general population.

Methods. 503 women from hereditary breast ovarian cancer families who had undergone RRSO aftergenetic counseling received a mailed questionnaire. 361 (71%) responded and 338 (67%) delivered completedata (cases). Controls were five randomly allocated age-matched controls per case (N=1690) from thepopulation-based Norwegian Nord-Trøndelag Health Study (HUNT-2).

Results. Mean age of cases and controls was 54.6 years at survey. Mean time since surgery was 5.3 years(median 6.0). Compared to controls, the RRSO group had more palpitations (p=0.02), constipation(p=0.01), pain and stiffness (p=0.02), osteoporosis (p=0.02) and musculoskeletal disease (p=0.01)even after adjustments for demographic factors including use of hormonal replacement therapy. The RRSOgroup had lower levels of depression (p b0.001) and total mental distress (p=0.002) compared to controls.In multivariate linear regression analyses, RRSO was associated with lower levels of depression (p b0.001)and total mental distress (p=0.002).

Conclusions. In this controlled observational study, we found more somatic morbidity such asosteoporosis, palpitations, constipation, musculoskeletal disease and pain and stiffness but lower levels ofmental distress among women who had undergone RRSO compared to controls.

© 2009 Elsevier Inc. All rights reserved.

Introduction

Ovarian cancer is the fifth most common cancer among women,and hereditary forms represent about 10% of cases [1]. The lifetimerisk of ovarian cancer is about 40% for BRCA1 and 18% for BRCA2mutation carriers, while the risk of sporadic ovarian cancer in thegeneral female population is 1.7% [2]. Risk-reducing salpingo-oophorectomy (RRSO) reduces the risk of ovarian cancer by 80% andthe risk of breast cancer considerably, but leads to an estimated 4%cumulative incidence of peritoneal cancer in 20 years after theprocedure [3–5]. BRCA mutation carriers are counseled to performRRSO before natural menopause, and in most cases, RRSO leads tosurgical menopause [6].

Hot flashes and vasomotor symptoms are well known symptomsassociated with estrogen deficiency in menopausal women [7].

, Sørlandet Hospital Arendal,ay. Fax: +47 37014041.M. Michelsen).

ll rights reserved.

Studies in post-RRSO samples have demonstrated more vasomotorsymptoms and poorer sexual functioning compared to controls whochose ovarian cancer surveillance programs instead of RRSO [8]. Theeffect of the sudden onset of menopause on bowel function is notwell-known, although at least one large study has assessed bowelhabits in relation to age and gender [9]. Non-oncologic morbidity andespecially somatic complaints are hardly studied in post-RRSOsamples. However, a small study by Fry et al. [10] reported moreaches and pains in women who had RRSO compared to women whoremained in an ovarian cancer screening program. A recent long-itudinal study of peri-menopausal Australian women with annualmeasurements showed a significant association between peri-meno-pause and aches and joint pain [11].

RRSO has been reported to be associated with a reduced fear ofdeveloping cancer, but also with a less favorable body image [12]. In alongitudinal study of 2500 middle-aged American women with anaverage risk of ovarian cancer, those with surgical menopause hadsignificantly higher depression scores than women with naturalmenopause [13]. Madalinska et al. [8] examined a Dutch sample of

129T.M. Michelsen et al. / Gynecologic Oncology 113 (2009) 128–133

women at high risk for ovarian cancer and compared those who hadRRSO to thosewho had gynecological surveillance. They found that theRRSO group had less cancer worries than the surveillance group [8]. Aprospective study by van Oostrom et al. [12] demonstrated that RRSOwas associated with decreasing levels of anxiety in the short term.However, at 5 years follow-up, there was a trend towards increasinglevels of anxiety, approaching the levels measured pre-surgery.

To the best of our knowledge, no studies have examined anxietyand depression levels after RRSO and compared the findings to that ofage-matched controls from the general population using internation-ally validated instruments. In addition, few studies have addressednon-oncologic long-term morbidity in post-RRSO samples.

This study of a sample of Norwegian women who had RRSO due toBRCAmutation testingor pedigree evidence of hereditarybreast ovariancancer, had three aims: 1) to examine levels of mental distress andprevalence of somatic complaints compared to age-matched femalecontrols from the general population. 2) To make internal comparisonsofmental distress and somatic complaints in RRSO subgroups accordingto age at surgery and history of cancer. 3) To study the strength ofassociations between RRSO, BRCA mutation status, anxiety and totalmental distress in the total sample (RRSO and control groups).

Methods

Sample selection

CasesThe sample consisted of 503 Norwegian women who had RRSO

after genetic counseling at the Department of Medical Genetics, theNorwegian Radium Hospital. All womenwere either carriers of BRCA1or BRCA2 mutation or at risk for hereditary breast/ovarian cancer dueto pedigree evidence and they were identified through surgicalrecords. The RRSO procedure was performed at three universityhospitals (Stavanger University Hospital, Ullevål University Hospitaland the Norwegian Radium Hospital) between 1985 and 2005.

In 2006, these women received a mailed invitation with anenclosed questionnaire covering data on anxiety and depression aswell as demographic, somatic, and lifestyle issues. The women werealso asked to see their regular general practitioner for physicalmeasures and blood tests. Non-respondents got one reminder after3 weeks. Altogether, 361 (72%) women responded, and the 338 (67%)who delivered complete data were included in the study. We had nomedical information about the non-respondents, and attritionanalyses therefore only included age at survey and age at RRSO.

ControlsThe Health Study of Nord-Trøndelag (HUNT-2), a rural and urban

Norwegian county, was carried out in 1995–97. All inhabitants aged20 years and abovewere invited to a general health study including twoquestionnaires and an appointed date for physical measures and bloodsamples, described in detail elsewhere [14]. Of the 46,709 womeninvited, 35,280 (76%) participated, and 28,025 were between 30 and79 years of age. We excluded women who reported hysterectomy(N=1835), and unilateral (N=1111) or bilateral (N=735) oophor-ectomy. Among the remaining 24,802 eligible controls, we randomlyselected five age-matched controls (N=1690) per case. The totalsample (RRSO and controls) consisted of 2028 women.

Measurements

Questionnaire items

Paired relations were defined as being married or cohabiting.Educational level was dichotomized into low (≤12 years) and high(N12 years) based on the number of completed school years. Paidwork consisted of those having income from employment or

independent business. Daily smoker was defined as those whoreported any daily cigarette smoking. Smoking was assessed becauseof documented associations with mental distress [15,16]. Hormonalreplacement therapy (HRT) was self-reported and defined as thecurrent use of systemic estrogen. All co-morbid diseases were basedon self-reported confirmative responses to the question: “Has yourdoctor ever said that you suffered from…?” to the names of specificdiseases. Diagnoses were not confirmed by medical records. Heart-burn, diarrhea, palpitations, nausea, constipation and dyspnea symp-toms were counted as present in those who reported “some orconsiderable distress” by such symptoms during the last year. Thesevariables were chosen as there are no reports on bowelmorbidity afterRRSO. Bowel morbidity as well as heartburn and nausea may beassociated with loss of estrogen and also with cancer and cancertreatment. Dyspnea and palpitations may be associated with bothmenopausal symptoms and anxiety.Musculo-skeletal disease consistedof long-term diseases not categorized as fibromyalgia, osteoarthritis orosteoporosis, and the diseases had to be diagnosed by a doctor. Painand stiffnesswasdefined as≥3months of continuouspain and stiffnessin muscles and joints the past year. Osteoporosis, musculo-skeletaldisease and pain and stiffness were included as there may beassociations between early menopause, loss of collagen and mus-culo-skeletal symptoms. BRCAmutation statuswas self-reported by thequestions: “Did you have surgery because of a positive genetic test?”We checked the medical records of the participants that did notrespond to this question. The data do not discriminate between thosewho had a negative mutation test of unknown significance and thosewith unknown test result. We did not have data on BRCA mutationstatus in the control group.

Rating scales

The Hospital Anxiety and Depression Scale (HADS) consists of thedepression (HADS-D) and the anxiety (HADS-A) subscale. Each subscalehas 7 items that are rated from 0 (not present) to 3 (maximally present)[17]. These subscales may be added to calculate HADS-total (HADS-T)[18]. TheHADS-Aand theHADS-D scores both range from0 to21, and theHADS-T scores range from 0 to 42. Higher scores represent highersymptom loads. Thepsychometricproperties of theHADShavebeenwelldocumented [19]. In the regression analyses, we performed multipleregression analyses with HADS-A, HADS-D and HADS-T as dependentvariables. We did not include HADS-D as a covariate when analyzingHADS-A or vice versa as the two variables were highly correlated(Pearson's r=0.60). Some cancer researchers have claimed that theHADS is a unidimensional scale, and that the HADS-T forms a higher-order single factor structure corresponding topsychologicaldistresswitha common variance shared by both of the subscales (HADS-A andHADS-D) [18,20]. We therefore studied HADS-T in addition to the subscales.Internal consistency of the HADS-A was α=0.84, the HADS-D α=0.78and theHADS-Tα=0.81 in theRRSOgroup, andα=0.84of theHADS-A,α=0.79 of theHADS-D andα=0.83 of theHADS-T in the control group.

Statistical analysis

Data were analyzed with SPSS-PC 15.0. Due to skewed distribu-tions, differences between the RRSO and control groups in HADS-A,HADS-D and HADS-T were calculated with the Mann–Whitney U test.Other continuous data were analyzed by t-tests, and categorical datawere analyzed with Pearson's χ2. Significant differences on contin-uous variables and 2×2 contingency tables were calculated as effectsizes (ES) and values N0.40 were considered as clinically significant[21,22]. The internal consistency of scales was tested with Cronbach'scoefficient α.

When comparing the RRSO and control groups on mental distressand somatic complaints, we adjusted for having had cancer and use ofHRT.When comparing the RRSO subgroups based on surgery before or

Table 1Demographic characteristics of the RRSO and control groups

RRSO group (N=338) Control group (N=1,690) p value ES#

Mean (SD) Mean (SD)

Age 54.6 (9.3) 54.6 (9.4) 0.98Age at RRSO 48.5 (8.3) –

Follow-up after RRSO 5.3 (3.3) –

N/total (%) N/total (%)Paired relations 294/338 (87) 1,298/1,688 (77) b0.001 0.26Level of education b0.001 0.60≤12 years 196/335 (59) 1,368/1,616 (85)N12 years 139/335 (41) 248/1,616 (15)

Paid work 212/338 (63) 962/1,690 (57) 0.05History of cancer 101/338 (30) 83/1,690 (5) b0.001 0.71Daily smoker 74/338 (22) 508/1,690 (30) 0.002 0.18HRT 136/338 (40) 270/1,690 (16) b0.001 0.55BRCA mutation positive 64/338 (19)BRCA mutation not positive 267/338 (79)Unknown mutation status 7/338 (2)

Abbreviations: RRSO, risk-reducing salpingo-oophorectomy; ES, effect size; SD, standard deviation; HRT, hormone replacement therapy; BRCA, breast cancer susceptibility gene.#ES: effect size, clinical significance was set at d≥0.40.

130 T.M. Michelsen et al. / Gynecologic Oncology 113 (2009) 128–133

after 50 years of age and presence of cancer, we adjusted for use ofHRT, follow-up time and age at survey. The BRCA mutation status datawere dichotomized into positive or not positive. That is, the cases withpositive BRCA mutation tests were compared to those who did nothave positive tests, regardless whether the test was negative or thetest had unknown significance.

We performed univariate and multivariate linear regressionanalyses with RRSO, use of HRT, history of cancer, paired relations,paid work, level of education, smoking, palpitations, constipation,musculoskeletal disease, osteoporosis, pain and stiffness and BRCAmutation status as independent variables and HADS-A, HADS-D andHADS-T as dependent variables in the total sample. The strength ofassociations in the regression analyses was expressed as standar-dized beta coefficients. As appropriate, 95% confidence intervals weregiven. The level of significance was set at p b0.05, and all tests weretwo-sided.

Ethics approval

The HUNT-2 studywas approved by the Regional Ethics Committeeof the Mid-Norway Health Region. The RRSO study was approved by

Table 2Comparison of anxiety, depression and somatic complaints in RRSO and control groups and

Total sample RRSO subgrou

RRSO(N=338)

Controls(N=1,690)

pa RRSOb50 year(N=195)

Median (range) Median (range) Median (rangeHADS-total 7.0 (29) 7.0 (37) 0.002 7.0 (29)HADS-anxiety 4.0 (21) 4.0 (20) 0.52 5.0 (16)HADS-depression 2.0 (16) 3.0 (17) b0.001 2.0 (16)

N/total (%) N/total (%) N/total (%)Heartburn 93/338 (28) 485/1,690 (29) 0.44 51/195 (26)Diarrhea 67/338 (20) 233/1,690 (14) 0.12 38/195 (38)Palpitations 98/338 (29) 361/1,690 (21) 0.02 66/195 (34)Nausea 60/338 (18) 184/1,690 (11) 0.15 36/195 (19)Constipation 116/338 (34) 419/1,690 (25) 0.01 70/195 (36)Dyspnea 32/338 (10) 121/1,690 (7) 0.20 16/195 (8)Pain and stiffness 177/338 (52) 953/1,690 (56) 0.02 102/195 (52)Osteoporosis 27/338 (8) 54/1,690 (3) 0.02 10/195 (5)Musculosk. dis. 44/338 (13) 108/1,690 (6) 0.01 26/195 (13)

Abbreviations: RRSO, risk-reducing salpingo-oophorectomy; SD, standard deviation; HADS,Musculosk. dis., musculoskeletal disease.Differences between the RRSO and control groups in HADS-A, HADS-D and HADS-T were caχ2. Adjustments were performed by using linear and logistic regression, respectively.

a p-values adjusted for having had cancer and current use of HRT.b p-values adjusted for current use of HRT, follow-up time and age at survey.

the Regional Ethics Review Board of Southern Norway, the NorwegianData Inspectorate and the Review Board of the Norwegian RadiumHospital. The RRSO sample and the participants of the HUNT-2 studyall delivered written informed consent.

Results

Attrition analysis

Mean age in the RRSO group in this study was 54.6 (SD 9.3) years,while mean age among invited non-participants was 54.4 (SD 9.5)years (p=0.83). Mean age at surgery was 48.5 (SD 8.2) years and 48.0(SD 8.8) years in the RRSO group and among non-participants,respectively (p=0.53). No other clinical data were available for moreextensive attrition analyses, and in 14 non-participants we did nothave data on age at surgery.

Demographic findings

Mean age at survey was 54.6 (SD 9.3) years in the RRSO group and54.6 (SD 9.4) years in the control group (Table 1). Mean age at RRSO

in RRSO subgroups

ps

s RRSO ≥50 years(N=143)

pb Cancer positive(N=101)

Cancer negative(N=237)

pb

) Median (range) Median (range) Median (range)6.0 (28) 0.69 7.0 (26) 6.0 (29) 0.183.0 (21) 0.64 5.0 (16) 4.0 (21) 0.232.0 (15) 0.82 2.0 (11) 2.0 (16) 0.22

N/total (%) N/total (%) N/total (%)42/143 (29) 0.18 29/101 (29) 64/237 (27) 0.9029/143 (20) 0.91 26/101 (26) 41/237 (17) 0.0932/143 (22) 0.01 29/101 (29) 69/237 (29) 0.9024/143 (17) 0.91 28/101 (28) 32/237 (14) b0.00146/143 (32) 0.71 32/101 (32) 84/237 (35) 0.9816/143 (11) 0.79 13/101 (13) 19/237 (8) 0.2475/143 (52) 0.25 51/101 (51) 126/237 (53) 0.5317/143 (12) 0.29 10/101 (10) 17/237 (7) 0.9718/143 (13) 0.16 15/101 (15) 29/237 (12) 0.54

hospital anxiety depression scale; HADS-total, total mental distress measured by HADS;

lculated with Mann–Whitney U test. The categorical data were analyzed with Pearson's

Table 3Linear regression analyses of independent variables in relation to HADS-anxiety score (dependent variable) in the total sample (RRSO and controls)

Univariate analysis Multivariate analysis

Standardized beta p Standardized beta p

RRSO (controls reference) 0.02 0.49 −0.03 0.26Non-paired relations (paired relations=reference) 0.007 0.05 −0.002 0.93≤12 years of education (N12=reference) 0.05 0.001 0.03 0.19Not in paid work (paid work=reference) 0.08 0.04 0.06 0.01History of cancer (no cancer=reference) 0.05 0.001 0.05 0.03Daily cigarette smoking (not daily=reference) 0.08 b0.001 0.07 0.001Palpitations (not palpitations=reference) 0.24 b0.001 0.22 b0.001Constipation (no constipation=reference) 0.14 b0.001 0.11 b0.001Musculoskeletal disease (no disease=reference) 0.09 0.29 0.02 0.28Osteoporosis (no osteoporosis=reference) 0.02 b0.001 −0.007 0.74Pain and stiffness (not=reference) 0.17 0.01 0.10 b0.001Use of HRT (no HRT=reference) 0.06 0.06 0.03 0.18BRCA mutation positive (no pos BRCA=reference) 0.04 0.07 0.05 0.05

Abbreviations: HADS, hospital anxiety depression scale; RRSO, risk-reducing salpingo-oophorectomy; HRT, hormonal replacement therapy; BRCA, breast cancer susceptibility gene;No pos BRCA, no positive BRCA mutation test.

131T.M. Michelsen et al. / Gynecologic Oncology 113 (2009) 128–133

was 48.5 (SD 8.3) years and mean follow-up time was 5.3 (SD 3.3)years (Table 1). The RRSO group was significantly more often in pairedrelations (87% versus 77%, ES=0.26) and a larger proportion hadmore than 12 years education (41% versus 15%, ES=0.60) comparedto controls (Table 1). The RRSO group also had significantly morecancer (30% versus 5%, ES=0.71), fewer daily smokers (22% versus30%, ES=0.18) and more use of HRT (40% versus 16%, ES=0.55)(Table 1). In the RRSO group, 64/338 (19%) reported a positivemutation test prior to surgery and 267/338 (79%) reported a negativetest. Our data do not discriminate between negative test and non-testable mutations. In 7/338 (2%), the BRCAmutation status could notbe documented from the medical records.

Anxiety, depression and somatic complaints

After adjustments for having had cancer and current use of HRT,the RRSO group had similar levels of anxiety and significantly lowerlevels of depression and total mental distress (HADS-T) compared tothe control group (Table 2). The RRSO group had significantly morepalpitations (ES=0.19), constipation (ES=0.20), pain and stiffness(ES=0.08), more musculoskeletal disease (ES=0.24) and osteoporo-sis (ES=0.23) than the control group (Table 2).

Internal comparisons of RRSO subgroups

The RRSO subgroup that underwent surgery before the age of50 years had more palpitations than those who had surgery at alater age (ES=0.27). The RRSO subgroup with a history of cancer

Table 4Linear regression analyses of independent variables in relation to HADS-depression score (d

Univariate analysis

Standardized beta

RRSO (controls reference) −0.10Non-paired relations (paired relations=reference) 0.02≤12 years of education (N12=reference) 0.08Not in paid work (paid work=reference) 0.17History of cancer (no cancer=reference) 0.03Daily cigarette smoking (not daily=reference) 0.04Palpitations (not palpitations=reference) 0.15Constipation (no constipation=reference) 0.06Musculoskeletal disease (no disease=reference) 0.25Osteoporosis (no osteoporosis=reference) 0.01Pain and stiffness (not=reference) 0.13Use of HRT (no HRT=reference) 0.02BRCA mutation positive (no pos BRCA=reference) −0.05

Abbreviations: HADS, hospital anxiety depression scale; RRSO, risk-reducing salpingo-oophoNo pos BRCA, no positive BRCA mutation test.

had significantly more nausea than those without such a history(ES=0.35).

Associations with anxiety, depression and total mental distress

In univariate analyses, higher levels of HADS-A were significantlyassociated with not having paid work, history of cancer, daily cigarettesmoking, palpitations, constipation, musculoskeletal disease, pain andstiffness and use of HRT (Table 3). In the multivariate analyses, higherlevels of HADS-A were significantly associated with not having paidwork, history of cancer, daily cigarette smoking, palpitations,constipation and pain and stiffness, while being a BRCA mutationcarrier versus not having a positive BRCA mutation test almostreached statistical significance (Table 3).

In univariate analyses, higher levels of HADS-D were significantlyassociatedwith belonging to the control group versus belonging to theRRSO group, lower levels of education, not having paid work,palpitations, constipation, musculoskeletal disease, pain and stiffnessand not having a positive BRCA mutation test versus being a BRCAmutation carrier. (Table 4). In multivariate analyses, higher levels ofHADS-D were significantly associated with belonging to the controlgroup versus belonging to the RRSO group, not having paid work,history of cancer, palpitations, musculoskeletal disease and pain andstiffness (Table 4).

In univariate analyses, higher levels of HADS-T were significantlyassociated with not having paid work, daily cigarette smoking, palpi-tations, constipation, musculoskeletal disease and pain and stiffness(Table 5). In multivariate analyses, higher levels of HADS-T were

ependent variable) in the total sample (RRSO and controls)

Multivariate analysis

p Standardized beta p

b0.001 −0.12 b0.0010.39 0.001 0.96

b0.001 0.03 0.25b0.001 0.15 b0.0010.23 0.06 0.010.08 0.03 0.17

b 0.001 0.15 b 0.0010.006 0.04 0.08

b0.001 0.06 0.0070.64 −0.006 0.80

b0.001 0.06 0.010.50 0.02 0.330.03 −0.006 0.82

rectomy; HRT, hormonal replacement therapy; BRCA, breast cancer susceptibility gene;

Table 5Linear regression analyses of independent variables in relation to HADS-total score (dependent variable) in the total sample (RRSO and controls)

Univariate analysis Multivariate analysis

Standardized beta p Standardized beta p

RRSO (controls reference) − 0.02 0.08 − 0.08 0.002Non-paired relations (paired relations=reference) 0.02 0.49 0.002 0.94≤ 12 years of education (N 12=reference) 0.05 0.05 0.03 0.17Not in paid work (paid work=reference) 0.13 b0.001 0.11 b0.001History of cancer (no cancer=reference) 0.04 0.05 0.06 0.009Daily cigarette smoking (not daily=reference) 0.07 0.002 0.06 0.004Palpitations (no palpitations=reference) 0.23 b0.001 0.21 b0.001Constipation (not constipation=reference) 0.12 b0.001 0.09 b0.001Musculoskeletal disease (no disease=reference) 0.11 b0.001 0.05 0.04Osteoporosis (no osteoporosis=reference) 0.02 0.95 − 0.007 0.76Pain and stiffness (not=reference) 0.17 b0.001 0.09 b0.001Use of HRT (no HRT=reference) 0.04 0.05 0.03 0.15BRCA mutation positive (no pos BRCA=reference) 0.00 0.99 0.03 0.28

Abbreviations: HADS, hospital anxiety depression scale; RRSO, risk-reducing salpingo-oophorectomy; HRT, hormonal replacement therapy; BRCA, breast cancer susceptibility gene;No pos BRCA, no positive BRCA mutation test.

132 T.M. Michelsen et al. / Gynecologic Oncology 113 (2009) 128–133

significantly associated with belonging to the control group versusbelonging to the RRSO group, not having paid work, history of cancer,daily smoking, palpitations, constipation, musculoskeletal disease andpain and stiffness (Table 5).

Discussion

The RRSO group had more somatic symptoms than controls. TheRRSO subgroup with surgery before the age of 50 years hadsignificantly more palpitations, and the subgroup with cancer hadsignificantly more nausea than the rest of the RRSO group. The RRSOgroup had significantly less depression (HADS-D) and total mentaldistress (HADS-T) compared to controls. In multivariate analyses,RRSO versus controls was significantly associated with lower levels ofdepression and total mental distress.

As reported by Madalinska et al. [8], the RRSO group in this studyhad more palpitations, which may be related to vasomotor symptomsafter surgical menopause. However, palpitations are also associatedwith increased anxiety levels, as symptoms of autonomic arousal(palpitations, sweating, trembling or dry mouth) are common parts ofthe anxiety syndrome [23].

Peri- and postmenopausal women have been reported to haveincreased prevalence of bowel dysfunction and constipation, althoughan aging effect cannot be ruled out [24]. The data regarding bowelfunction and relation to menopause seem to be scarce and somewhatcontradictory, and bowel function is affected by both parity, sex andrace in addition to age [25]. Concerning women who had RRSO, ourfinding of more constipation compared to controls is new, and furtherresearch on the effect of surgical menopause on bowel function isneeded.

The RRSO group reported significantly more osteoporosis than thecontrol group. This is in accordance with Melton et al. [26,27], whoreported from longitudinal American studies that bilateral oophor-ectomy both pre- and postmenopausally was associated withincreased risk of fractures. However, no previous studies haveexamined the association between RRSO and osteoporosis.

The women in the RRSO group reported more pain and stiffnessthan did controls, and this finding may be associated with osteoporo-sis. These symptoms may also be explained by estrogen deficiencywhich is associated with loss of collagen [28], and thus could increasethe risk of other musculoskeletal diseases. This is in accordance withour finding that RRSO was associated with long-standing musculos-keletal diseases, such as fibromyalgia and osteoarthritis.

Although van Oostrom et al. [12] documented lower levels ofanxiety in post-RRSO women at short term, they found increasinglevels of anxiety approaching pre-surgery measures after 5 years [12].We did not find an association between RRSO and anxiety, but

interestingly the association between being a BRCA mutation carrierand higher levels of anxiety was borderline significant. At the sametime, RRSO was associated with lower levels of depression and totalmental distress. In general, anxiety is a reaction to danger in the future,while depression is a reaction to loss [29].With this interpretation, onemight assume that the BRCAmutation carriers stillmayhaveworries offuture cancer and early death, while the major part of the RRSO grouphas dealtwith the initial loss constituted by theHBOC diagnosis, loss ofaffected family members, and loss of their ovaries. The finding is inaccordance with Liavaag et al. [30], who studied long term survivorsafter ovarian cancer and found lower levels of depression in the cancergroup compared to normative controls.

The RRSO group had a higher level of education, included a lowerproportion of smokers and a higher proportion in paid work andpaired relations compared to controls. The lifestyle findings may havebeen caused by a response shift [31], indicating that the RRSO groupmay have adapted a healthier lifestylewith less smoking. Also, womenwho undertake genetic testing and RRSOmay be self-selected. Lermanet al. [32] demonstrated that rates of BRCA mutation testing werehigher in families with higher socioeconomic status, although theirsample may differ from our study population, as genetic and surgicalhealth services are free of cost in Norway.

Strengths and limitations

Use of the HADS and age-matched normative controls areconsidered as strengths in this study. The controls were drawn fromHUNT-2, a large population study performed in 1995–97, in a countyconsidered representative of the Norwegian population [14]. Theresponder rate in the RRSO group of 72% at a median of 5 years follow-up is considered as good, as the questionnaires also included sensitivesexual and intimate matters.

The interpretation of our findings should also take the study'slimitations into consideration. Self-report measures may over- orunderestimate levels of mental distress and somatic complaints, butwe have no reason to believe that such measures induced systematicbias between the RRSO and the control groups. The external validity ofthe study is limited by the fact that we were unable to perform athorough attrition analysis. The cross-sectional design of the study didnot allow for causal interpretations. The control material does notcontain information about BRCA mutation status. The Nord-TrøndelagCounty does not have known founder mutations, and the prevalenceof BRCA mutations is 0.1–0.2% in the general population [33].Therefore, approximately 3 out of 1690 controls could be BRCAmutation carriers, although they probably would have been excludedtogether with non-eligible controls if they had undergone bilateraloophorectomy. Furthermore, the data do not discriminate between

133T.M. Michelsen et al. / Gynecologic Oncology 113 (2009) 128–133

those who had a negative mutation test of unknown significance andthose with unknown test results. The low proportion of BRCAmutation carriers may be explained by limited access to completemutation testing at the time of the study, as initial genetic testing wasonly aimed at Norwegian BRCA founder mutations. Full BRCA1 andBRCA2 mutation testing was just recently made available in Norway.

Women with RRSO may be self-selected in regard to highereducation, more paid work and a healthier lifestyle. Such selectionbias may reduce the risk of mental distress and somatic complaints. Aswe included post-RRSO patients whowere alive at a median of 6 yearsafter surgery, the data set may be influenced by a survival bias. Since29% of cases have a history of cancer, it is likely that somewomen fromthe initial RRSO cohort may be deceased, and we may have invited anRRSO group who was healthier than the cohort who initially hadsurgery. If so, the survival bias may weaken the association betweenRRSO and mental distress and somatic complaints. In spite ofadjustments, we cannot exclude selection and survival biases.

Conclusion

We have shown that RRSO in women at risk for hereditary breastovarian cancer was significantly associated with lower levels ofdepression and total mental distress compared to controls from thegeneral population. The RRSO group had more somatic morbidityincluding osteoporosis and musculoskeletal diseases as well assymptoms like palpitations, constipation and pain and stiffness.These findings need to be reproduced in future studies.

Conflict of interest statementThe authors declare that there are no conflicts of interest.

Acknowledgments

HUNT is a collaboration between HUNT Research Centre, Faculty ofMedicine, Norwegian University of Science and Technology (NTNU,Verdal), Norwegian Institute of Public Health, and Nord-TrøndelagCounty Council.

Funding sources: Trond Melbye Michelsen, MD holds a researchcareer grant from Sørlandet Hospital and the National Resource Centrefor Women's Health, Rikshospitalet.

References

[1] Narod SA, Risch H, Moslehi R, Dorum A, Neuhausen S, Olsson H, et al. Oralcontraceptives and the risk of hereditary ovarian cancer. Hereditary OvarianCancer Clinical Study Group. N Engl J Med 1998;339(7):424–8.

[2] Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol2007;25(11):1329–33.

[3] Finch A, Beiner M, Lubinski J, Lynch HT, Moller P, Rosen B, et al. Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers inwomen with a BRCA1 or BRCA2 Mutation. JAMA 2006;296(2):185–92.

[4] Narod SA. Modifiers of risk of hereditary breast cancer. Oncogene 2006;25(43):5832–6.

[5] Kauff ND, Domchek SM, Friebel TM, Robson ME, Lee J, Garber JE, et al. Risk-reducingsalpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast andgynecologic cancer: a multicenter, prospective study. J Clin Oncol 2008;26(8):1331–7.

[6] Domchek SM, Weber BL. Clinical management of BRCA1 and BRCA2 mutationcarriers. Oncogene 2006;25(43):5825–31.

[7] Guthrie JR, Dennerstein L, Taffe JR, Lehert P, Burger HG. Hot flushes during themenopause transition: a longitudinal study in Australian-born women. Meno-pause 2005;12(4):460–7.

[8] Madalinska JB, Hollenstein J, Bleiker E, van BM, Valdimarsdottir HB, Massuger LF,et al. Quality-of-life effects of prophylactic salpingo-oophorectomy versusgynecologic screening among women at increased risk of hereditary ovariancancer. J Clin Oncol 2005;23(28):6890–8.

[9] Harari D, Gurwitz JH, Avorn J, Bohn R, Minaker KL. Bowel habit in relation to ageand gender. Findings from the National Health Interview Survey and clinicalimplications. Arch Intern Med 1996;156(3):315–20.

[10] Fry A, Busby-Earle C, Rush R, Cull A. Prophylactic oophorectomy versusscreening: psychosocial outcomes in women at increased risk of ovarian cancer.Psychooncology 2001;10(3):231–41.

[11] Szoeke CE, Cicuttini FM, Guthrie JR, Dennerstein L. The relationship of reports ofaches and joint pains to the menopausal transition: a longitudinal study.Climacteric 2008;11(1):55–62.

[12] van Oostrom I, Meijers-Heijboer H, Lodder LN, Duivenvoorden HJ, Van Gool AR,Seynaeve C, et al. Long-term psychological impact of carrying a BRCA1/2mutationand prophylactic surgery: a 5-year follow-up study. J Clin Oncol 2003;21(20):3867–74.

[13] McKinlay JB, McKinlay SM, Brambilla D. The relative contributions of endocrinechanges and social circumstances to depression in mid-aged women. J Health SocBehav 1987;28(4):345–63.

[14] Holmen J, Midthjell K, Kruger Ø, Langhammer A, Homen TL, Bratberg GH, et al. TheNord-Trøndelag Health Study 1995–97 (HUNT 2): objectives, contents, methodsand participation. Nor Epidemiol 2003;13:19–32.

[15] Glassman AH, Helzer JE, Covey LS, Cottler LB, Stetner F, Tipp JE, et al. Smoking,smoking cessation, and major depression. JAMA 1990;264(12):1546–9.

[16] Glassman AH. Cigarette smoking: implications for psychiatric illness. Am JPsychiatry 1993;150(4):546–53.

[17] Bjelland I, Dahl AA, Haug TT, Neckelmann D. The validity of the hospital anxietyand depression scale. An updated literature review. J Psychosom Res 2002;52(2):69–77.

[18] Smith AB, Wright EP, Rush R, Stark DP, Velikova G, Selby PJ. Rasch analysis of thedimensional structure of the hospital anxiety and depression scale. Psychooncol-ogy 2006;15(9):817–27.

[19] Mykletun A, Stordal E, Dahl AA. Hospital anxiety and depression (HAD) scale:factor structure, item analyses and internal consistency in a large population. Br JPsychiatry 2001;179:540–4.

[20] Smith AB, Selby PJ, Velikova G, Stark D, Wright EP, Gould A, et al. Factor analysis ofthe hospital anxiety and depression scale from a large cancer population. PsycholPsychother 2002;75(Pt 2):165–76.

[21] Cohen J. Statistical power analysis for the behavioral sciences. Edition 2 ed.Hillsdale, NJ: Lawrence Erlabaum Associates; 1988.

[22] Lipsey MW, Wilson DB. Practical meta-analysis. CA: Sage: Thousand Oaks; 2001.[23] Tyrer P, BaldwinD. Generalised anxiety disorder. Lancet 2006;368(9553):2156–66.[24] Triadafilopoulos G, Finlayson M, Grellet C. Bowel dysfunction in postmenopausal

women. Women Health 1998;27(4):55–66.[25] Zutshi M, Hull TL, Bast J, Hammel J. Female bowel function: the real story. Dis

Colon Rectum 2007;50(3):351–8.[26] Melton III LJ, Khosla S, Malkasian GD, Achenbach SJ, Oberg AL, Riggs BL. Fracture

risk after bilateral oophorectomy in elderly women. J Bone Miner Res 2003;18(5):900–5.

[27] Melton III LJ, Crowson CS, Malkasian GD, O, Fallon WM. Fracture risk followingbilateral oophorectomy. J Clin Epidemiol 1996;49(10):1111–5.

[28] Castelo-Branco C, Pons F, Gratacos E, Fortuny A, Vanrell JA, Gonzalez-Merlo J.Relationship between skin collagen and bone changes during aging. Maturitas1994;18(3):199–206.

[29] Hales RE, Yudosky SC, Talbott JA. The American Psychiatric Press textbook ofpsychiatry. 3 ed. Washington DC: American Psychiatric Press; 1999.

[30] Liavaag AH, Dorum A, Fossa SD, Trope C, Dahl AA. Controlled study of fatigue,quality of life, and somatic and mental morbidity in epithelial ovarian cancersurvivors: how lucky are the lucky ones? J Clin Oncol 2007;25(15):2049–56.

[31] Schwartz CE, Sprangers MAG. Adaptation to changing health: response shift inquality of life research. Washington, DC: American Psychological Association;2000.

[32] Lerman C, Narod S, Schulman K, Hughes C, Gomez-Caminero A, Bonney G, et al.BRCA1 testing in families with hereditary breast-ovarian cancer. A prospectivestudy of patient decision making and outcomes. JAMA 1996;275(24):1885–92.

[33] Haber D. Prophylactic oophorectomy to reduce the risk of ovarian and breastcancer in carriers of BRCA mutations. N Engl J Med 2002;346(21):1660–2.