What happens after menopause? (WHAM): A prospective controlled study of vasomotor symptoms and menopause-related quality of life 12months after premenopausal risk-reducing salpingo-oophorectomy

What happens after menopause? (WHAM): A prospective controlled

study of vasomotor symptoms and menopause-related quality of life

12 months after premenopausal risk-reducing salpingo-oophorectomy

Martha Hickey

⁎

, Katrina M. Moss

, Efrosinia O. Krejany

, C. David Wrede

a,d

, Alison Brand

e,f

, Judy Kirk

Heather L. Symecko

, Susan M. Domchek

, Trevor Tejada-Berges

, Alison Trainer

, Gita D. Mishra

Department of Obstetrics and Gynaecology, University of Melbourne and the Royal Women's Hospital, Melbourne, Victoria, Australia

Centre for Longitudinal and Life Course Research, School of Public Health, University of Queensland, Brisbane, Queensland, Australia

Gynaecology Research Centre, The Royal Women's Hospital, Melbourne, Victoria, Australia

Gynae-oncology and Dysplasia Unit, The Royal Women's Hospital, Melbourne, Victoria, Australia

Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia

Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia

Basser Center for BRCA, University of Pennsylvania, Philadelphia, USA

Gynaecological Oncology Service, Chris O'Brien Lifehouse, Sydney, New South Wales, Australia

Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

HIGHLIGHTS

• Vasomotor symptoms increase by 3 months following premenopausal RRSO and persist but do not worsen by 12 months.

• Almost all women report these vasomotor symptoms as “mild”.

• Hormone therapy reduces but does not resolve vasomotor symptoms after RRSO.

• Hormone therapy improves menopause related quality of life but not to pre-RRSO levels.

abstractarticle info

Article history:

Received 24 May 2021

Received in revised form 15 July 2021

Accepted 18 July 2021

Available online xxxx

Objective. To measure menopausal symptoms and quality of life up to 12 months after risk-reducing salpingo-

oophorectomy (RRSO) and to measure the effects of hormone therapy.

Methods. Prospective observational study of 95 premenopausal women planning RRSO and a comparison

group of 99 who retained their ovaries. Vasomotor symptoms and menopausal-related qual ity of life (QoL)

were measured by the Menopause-Speciﬁc QoL Intervention scale at baseline, 3, 6 and 12 months. Chi-square

tests measured differences in prevalence of vasomotor symptoms between RRSO vs the comparison group and

by hormone therapy use. Change in QoL were examined with multilevel modelling.

Results. Three months after RRSO hot ﬂush prevalence increased from 5.3% to 56.2% and night sweats from

20.2% to 47.2%. Symptoms did not worsen between 3 and 12 months and remained unchanged in the comparison

group (p<0.001). After RRSO, 60% commenced hormone therapy. However, 40% of hormone therapy uses con-

tinued to experience vasomotor symptoms. After RRSO, 80% of non-hormone therapy users reported vasomotor

symptoms. Regardless of hormone therapy use, 86% categorized their vasomotor symptoms as “mild” after RRSO.

Following RRSO, Menopause-related QoL deteriorated but was stable in the comparison group (adjusted coefﬁ-

cient = 0.75, 95%CI = 0.55-0.95). After RRSO, QoL was better in hormone therapy users vs non-users (adjusted

coefﬁcient = 0.49, 95%CI = 0.20-0.78).

Conclusions. Vasomotor symptoms inc rease by 3 months after RRSO but do not worsen over the next 12

months. Hormone Therapy reduces but does not resolve vasomotor symptoms and may improve QoL, but not

to pre-oophorectomy levels.

Keywords:

BRCA1/2

Hormone therapy

Menopause-related quality of life

Oophorectomy

Vasomotor symptoms

Gynecologic Oncology xxx (xxxx) xxx

⁎ Corresponding author at: University of Melbourne, Department of Obstetrics and Gynaecology, Research Precinct, Level 7, The Royal Women's Hospital, Cnr or Grattan Street and

Flemington Road, Parkville, VIC 3052, Australia.

E-mail address: hickeym@unimelb.edu.au (M. Hickey).

YGYNO-978538; No. of pages: 7; 4C:

https://doi.org/10.1016/j.ygyno.2021.07.029

Contents lists available at ScienceDirect

Gynecologic Oncology

journal homepage: www.elsevier.com/locate/ygyno

Please cite this article as: M. Hickey, K.M. Moss, E.O. Krejany, et al., What happens after menopause? (WHAM): A prospective controlled study of

vasomotor symptoms and menop..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2021.07.029

1. Introduction

Ovarian cancer is the ﬁfthmostcommonfemalecancerwithsurvival

rates below 50% at 5 years [1]. Carriers of pathogenic variants in genes

that increase hereditary risk for ovarian cancer, such as brca1 and

brca2 have an elevated risk of ovarian cancer of up to 44% [2,3]. With in-

creasing access to rapid, low-cost gene sequencing, more women are

identiﬁed with these pathogenic va riants and onl y risk-reducing

salpingo-oophorectomy (RRSO) reduces ovarian cancer and all-cause

mortality in this population [4,5]. The National Comprehensive Cancer

Network recommends RRSO at age 35–40 years in women with

BRCA1 and 40–45 for those with BRCA2 mutations [6].

Few prospective studies have measured vasomotor symptoms

(VMS) or other aspects of menopause-related qu ality of life (QoL)

after premenopausal RRSO. Cross-sectional and retrospective studies

consistently report that premenopausal oophorectomy leads to more

sudden, severe and/or persistent VMS compared to natural menopause

[7,8]. However the prospective impact on menopause-related QoL is un-

certain [9,10].

Hormone therapy (HT) is the most effective treatment for VMS and

may improve menopause-related QoL in postmenopausal women [11].

Whilst HT is recommended after RRSO for those without contraindica-

tions, uptake is suboptimal [12]. The efﬁcacy of HT for VMS and quality

of life after RRSO is uncertain [9]. For high-risk women, concerns about

managing menopausal symptoms after RRSO are a barrier to potentially

life-saving surgery [13].

The aim of this study was to measure the prevalence, trajectories

and severity (as measured by bother) of vasomotor and other meno-

pausal symptoms following RRSO to inform clinical decision making

and patient care. This study focused on the ﬁrst 12 months after RRSO

and recruited a comparison group of same-aged premenopausal

women who retained their ovaries and were predominantly at popula-

tion risk of ovarian cancer. There were three speciﬁc aims: (1) to mea-

sure the prevalence and degree of bother from VMS, (2) to investigate

changes in menopause-related QoL and (3) to compare the prevalence

and bother of VMS and menopause related QoL between HT users and

non-HT users.

2. Methods

2.1. Study design and population

This was a multicenter prospective observational study. The RRSO

group were premenopausal women at high risk of ovarian cancer plan-

ning RRSO, identiﬁed by treating clin icians in gynaecology-oncology

and familial cancer centers. The comparison group were a se lf-

referring, community-based sample of similar-aged premenopausal

women not planning oophorectomy or pregnancy in the next 2 years.

Premenopausal status was conﬁrmed by regular menstrual cycles,

days 2 to 6 Follicle Stimulating Hormone (FSH) ≤15 IU/L and estradiol

>100 pmol/L [14]. Exclusions for both groups included pregnancy or

lactation in the past 3 months, unscheduled vaginal bleeding or use of

anti-estrogens [ 15

]. Participants were recruited from 5 sites, 4 in

Australia and 1 in the USA. All participants provided written informed

consent as pr eviously described [15]. Baseline data were collected

within 8 weeks of eligibility scre ening, and RRSO was scheduled be-

tween the baseline and 3 month study time-points [15].

2.2. Study assessments

Demographic data, medical, surgical, and gynaecological history, HT

and hormonal contraceptive use were documented, and questionnaires

were completed at the baseline, 3, 6 and 12 month study time-points.

Dates of administration, type and dose of systemic HT were self-

reported at each study time-point. All participants completed the

Menopause-Speciﬁc Quality of Life Intervention Version (MENQOL-I)

questionnaire [16]. The MENQOL-I captures 32 symptoms in four do-

mains: vasomotor (3 items – hot ﬂashes/ﬂushes, night sweats and

sweating), psychosocial (7 items), physical (19 items) and sexual (3

items) [16,17]. Participants indicated whether they experienced each

symptom “in the past week” (no or yes) and rated the degree of symp-

tom bother on a 7-point linear scale (from “not at all” to “extremely

bothered”). Domain scores are calculated as the average of the item re-

sponses within each domain, with higher scores equating to greater

both er. The total MENQ OL-I score is the average of the four domain

scores. The scale is validated and widely used [18,19]. Dichotomized re-

sponses (no/yes) to questions about hot ﬂashes and night sweats were

used to determine the prevalence of VMS. The degree of bother from

VMS was determined fr om the MENQOL-I vasomotor domain score,

whereby participants with scores between 2 and 5 were classiﬁed as

having “mild” bother and those with scores between 6 and 8 as having

“severe” bother [20].

2.3. Potential confounders

Potential confounders in the associations between RRSO and meno-

pausal symptoms included age at baseline, previous clinician diagnosed

anxiety or depression, body mass index (BMI) and smoking status at

baseline and 12 months. BMI was classiﬁed using WHO criteria as un-

derweight /normal (<25 kg/m

), overweight (25 to <30 kg/m

)or

obese (≥30 kg/m

). Smokers were categorized as non-smoker (never

smoked), ex-smoker (ceased before baseline) or current smoker

(smoker any time between baseline and 12 months).

2.4. Statistical analysis

Descriptive statistics were generated to check cell sizes in categorical

variables and distribution shape and outliers in continuous variables. A

small number of outliers were detected and winsorized (value reduced

so they were no longer outliers but maintained their rank within the

distribution). The differences in prevalence of VMS between the RRSO

and comparison groups, and between HT users and non-users were ex-

amined using Chi-square tests. Multilevel models (proc mixed) were

used to compare change over time, and differences at 12 months in

RRSO and comparison groups and HT users and non-users. Time

(months) centered at 12 months and continuous total MENQOL-I and

individual domain scores were analyzed. The unadjusted multilevel

models included time and either study group or HT use as the explana-

tory variables. The adjusted model was run twice, once with the base-

line value of the outcome variable and all covariates, and again with

only the covariates signiﬁcant at p < 0.10 (less stringent statistical sig-

niﬁcance criteria due to smaller sample size). Models were repeated

with the winsorized variables as a sensitivity analysis. Statistical signif-

icance was set at p < 0.05 and statistical analysis was conducted in SAS

(version 9.4, SAS Institute, North Carolina).

3. Results

3.1. Participant demographics

Of the 687 women screened between 2013 and 2019, n = 224 met

inclusion criteria a nd were willing to participate and 194 women

were included in this analysis (RRSO group: n = 94; comparison

group: n =99)(Fig. 1). Between the Baseline and 12 month study visits

30 of the 224 eligible participants were withdrawn from the study. This

included: (i) 18 who did not meet the inclusion criteria for Baseline es-

tradiol and/or FSH levels, (ii) 8 who revoked consent – prior to the 3

month (n = 2), 6 month (n = 2) and 12 month (n = 4) study visits,

(iii) 3 who were lost to follow-up – prior to the 6 month (n = 2) and

12 month (n = 1) study visits, and (iv) 1 who completed the two-

year study but did not attend the 3, 6 and 12 month study visits

(Fig. 1). Mean ages at baseline of the two groups were very similar

M. Hickey, K.M. Moss, E.O. Krejany et al. Gynecologic Oncology xxx (xxxx) xxx

(RRSO 41.5 +/− SD 5.1 years vs comparisons 40.8 +/-SD 5.8, p =

0.074) (Table 1). BMI and smoking status did not differ between groups

but more RRSO participants were overweight/obese (61% versus 46.5%;

p = 0.078) (Table 1). More participants in the RRSO group had a history

of breast cancer (11.6% vs 2%, p = 0.008) and one developed breast can-

cer during the study. Thirty-one percent of the RRSO group had concur-

rent hysterectomy with RRSO (Table 1). No occult ovarian cancers were

detec ted but one case of serous tubal intraepithelial carcinoma was

identiﬁed. None of the comparison group underwent oophorectom y

during the study period.

3.2. Use of systemic hormone therapy (HT)

No participants were using HT at baseline. After RRSO, 60% (57/95)

initiated HT, most (47/57, 82.5%) within 3 months of RRSO and all con-

tinued for 12 months. Only 10 (17.5%) delayed initiation of HT beyond 3

months after RRSO. Of those who did intiate HT within 3 months, 66%

(31/47) started HT with in the ﬁrst week after surgery. The es trogen

dose in HT was clinically determined. Of the 57 HT users, 23 (40.4%)

used oral estrogen formulations, 31 (54.4%) used transdermal estrogen

formulations and 3 (5.2%) used tibolone. Of those taking estrogen-

containing HT, most (45/57, 78.9%) took doses equivalent to 50 μg/day

or greater of transdermal estradiol or 1 mg/day or greater of oral estra-

diol. Only three participants (5.3%) took <50 μg/day. Over the study pe-

riod eight (14%) varied their HT dose - 7 increased the estrogen dose

and 1 decreased the dose. In one participant the HT dose was unknown.

Only 4 participants used vaginal estrogen after RRSO - two in addition to

systemic HT and two used vaginal estrogen alone.

3.3. Vasomotor symptoms (VMS)

The prevalence of VMS increased between baseline and 3 months

after RRSO (p < 0.001) and was signiﬁcantly higher than the compari-

son group at 3, 6 and 12 months (all p < 0.001) (Fig. 2). The overall

Women Screened for Eligibility (n = 687)

(a) Clinician-Referred (n = 313)

RRSO = 296; Comparison = 17

(b) Self-Referred (n = 374)

RRSO = 10; Comparison = 364

Excluded (n = 463)

(a) Inclusion / Exclusion Criteria Not Met (n = 168)

RRSO = 94; Comparison = 74

(b) Declined Participation (n = 117)

RRSO = 55; Comparison = 62

Screening (n = 143)

RRSO = 34; Comparison = 109

(d) Other Reasons (n = 35)

RRSO = 7; Comparison = 28

Enrolled at Baseline (n = 224)

RRSO = 116; Comparison = 108

Excluded (n = 18)

Baseline Screen Failure: FSH > 15 IU/L or E2 < 100 pmol/L

RRSO = 12; Comparison = 6

Pre-Oophorectomy (n = 206)

RRSO = 104; Comparison = 102

Excluded (n = 12)

(a) Lost To Follow-Up (n = 3)

RRSO = 2; Comparison = 1

(b) Revocation of Consent (n = 8)

RRSO = 6; Comparison = 2

RRSO = 1; Comparison = 0

Post-Oophorectomy at 12 months (n = 194)

RRSO = 95; Comparison = 99

Fig. 1. Participant Flowchart. Number of participant screenings, enrolments, withdrawals and exclusions relevant to the ﬁrst 12 months of the WHAM study. Women were either clinician-

or self-referred to one of ﬁve recruitment sites in Australia and the USA during 2013 to 2019. FSH = Follicle-Stimulating Hormone; E2 = Estradiol.

M. Hickey, K.M. Moss, E.O. Krejany et al. Gynecologic Oncology xxx (xxxx) xxx

prevalence of VMS was 55% which remained stable between 3 and 12

months (Fig. 2). Multilevel regression models, readjusted for baseline

values , age and BMI at baseline, previous depression or anxiety, and

smoking status showed tha t VMS severity (as measured by bother)

had increased by 3 months after RRSO and remained elevated at 12

months (Fig. 3 and Tables S1 and S2). In par ticipants with VMS at 3

months (n = 58), VMS bother was ca tegorized as “mi ld” in 86% and

as “moderate” or “severe” in only 14% (Table S3). This pattern of VMS

bother did not signiﬁcantly change over the 12-month follow-up period

(Table S3).

3.4. Menopause-related quality of life (QoL)

Overall menopause-related QoL worsened between baseline and 3

months in the RRSO group but not in the comparison group (Tables S1

and S2). The MENQOL-I subscale scores indicated that worsening QoL

after RRSO was driven by an increase in vasomotor, sexual, and physical

symptom domains. There were no differences between groups in the

psychosocial domain of the MENQOL-I (Tables S1 and S2). Results did

not differ when analyses were conducted using the winsorized variables

as a sensitivity analysis (data not shown).

3.5. Effects of hormone therapy (HT)

After RRSO, VMS were less common in HT users (60%) compared to

non-HT users (40%). However, VMS persisted despite HT use. At 3 months,

39.6% of HT users reported hot ﬂashesversus80.6%ofnon-HTusersand

this pattern persisted over 12 months (Fig. 4). At 3 months, there was little

difference between HT users and non-HT users in the prevalence of night

sweats (41.5% in HT users versus 55.6% in non-HT users), but by 6 months

the prevalence of night sweats was halved in HT users compared to non-

HT users (35.1% vs 68.6%) (Fig. 4). Multilevel models indicated that HT sig-

niﬁcantly reduced VMS bother at all time-points (Fig. 5 and Table S4). In

non-HT users, VMS bother remained constant over the 12-month follow-

up period (Fig. 5). Adjusted multilevel regression models showed that HT

improved overall QoL and sexual function compared to non-HT users

(Table S4). However, use of HT did not restore overall menopause-

related QoL or sexual function to baseline levels (Table S5). Use of HT did

not affect the physical or psychosocial domains of the MENQOL-I.

4. Discussion

This is the largest prospective studies of VMS after premenopausal

RRSO to include a premenopausal control group. Following RRSO, we

observed a substantial increase in the prevalence of VMS, which were

reported by around 40% of HT users and 80% of non-HT users by 3

months. These persisted and did not return to baseline levels by 12

months. However, the ov erall prevalence of VMS (50%), in cluding

those who did and did not take HT, was somewhat less than that re-

ported in population-based studies of the natural menopause transition

(75 to 85%) [21]. We observed that VMS were not inevitable after pre-

menopausal RRSO. Of the non-HT users around 20% reported no hot

ﬂashes and 45% no night sweats over 12-months.

Vasomotor symptoms are thought to be more severe following pre-

menopausal oophorectomy compared to natural menopause [22]. How-

ever, almost all WHAM RRSO participants described the severity of

VMS (as measured by bother) as “mild” (86%) and only 14% classiﬁed

their VMS as “moderate” or “severe

”, and this included HT users and

Table 1

Demographic characteristics of overall sample and by study group.

Characteristic (n, %) By Study Group

Overall

n = 194

Comparison

n =99

RRSO

n =95

Age (years) at baseline (mean, SD) 41.5 (5.1) 40.8 (5.8) 42.1 (4.2) 0.074

BMI (kg/m

) at baseline

< 25 (Under/Normal) 90 (46.4) 53 (53.5) 37 (39.0) 0.078

25 to <30 (Overweight) 60 (30.9) 29 (29.3) 31 (32.6)

≥ 30 (Obese) 44 (22.7) 17 (17.2) 27 (28.4)

Hysterectomy

No 159 (82.0) 95 (96.0) 64 (67.4) <0.001

Yes 35 (18.0) 4 (4.0) 31 (32.6)

Previous breast cancer at baseline

No 181 (93.3) 97 (98.0) 84 (88.4) 0.008

Yes 13 (6.7) 2 (2.0) 11 (11.6)

Pathogenic genetic variants

BRCA

No/unknown 117 (60.3) 94 (95.0) 23 (24.2) –

BRCA1 38 (19.6) 2 (2.0) 36 (37.9)

BRCA2 35 (18.0) 3 (3.0) 32 (33.7)

BRCA1 & 2 4 (2.1) 0 (0) 4 (4.2)

Lynch syndrome (MLH1, MSH6, PMS2)

No/unknown 189 (97.4) 98 (99.0) 91 (95.8) –

Yes 5 (2.6) 1 (1.0) 4 (4.2)

Other pathogenic variants (STK11, BRIP1)

No/unknown 192 (99.0) 99 (100) 93 (97.9) –

Yes 2 (1.0) 0 (0) 2 (2.1)

Hormonal contraception at baseline

No 115 (59.3) 53 (53.5) 62 (65.3) 0.097

Yes 79 (40.7) 46 (46.5) 33 (34.7)

Smoking status

Non-smoker 117 (60.3) 60 (60.6) 57 (60.0) 0.719

Ex-smoker 62 (32.0) 30 (30.3) 32 (33.7)

Smoked during WHAM 15 (7.7) 9 (9.1) 6 (6.3)

Chi-square test not performed where cell sizes were too small.

One RRSO and three comparison participants had hysterectomy prior to Baseline. One comparison participant underwent hysterectomy (ovaries retained)

during the follow-up period.

One RRSO participant developed breast cancer over the follow-up period.

Pathogenic genetic variants known to increase ovarian cancer risk.

M. Hickey, K.M. Moss, E.O. Krejany et al. Gynecologic Oncology xxx (xxxx) xxx

non-HT users. Whilst we did not have a control group transitioning nat-

ural menopause to compare VMS severity, population-based studies of

natural menopause using the same severity measure report that around

one quarter experience “moderate to severe” VMS [23,24]. Women con-

sidering RRSO are very concerned abou t the prospect of severe VMS

[13]. Together, our ﬁndings suggest that bothersome VMS are not inev-

itable after premenopausal RRSO and may not be worse than those ex-

perienced over the natural menopause transition. However, RRSO led to

a decline in overall, QoL in vasomotor, sexual and physical domains of

the MENQOL-I. Thus more information is needed about the se verity

and duration of VMS and effects on quality of life following RRSO com-

pared to those experienced transitioning natural menopause.

Following RRSO the uptake of HT was around 60% which is similar to

previous publications [25]. Use of HT was not randomized in this study

and it is likely that women with more troublesome VMS were more

likely to take HT. Consistent with previously published studies, we

foun d that HT reduced but did not fully resolve VMS after RRSO

[9,26,27]. At three months, around 40% of HT users continued to report

hot ﬂashes and HT had little impact on the prevalence of night sweats.

Compared to baseline, this represented an 8-fold increase in the preva-

lence of hot ﬂashes at three months despite HT use. Over the natural

menopause transition HT reduces VMS by around 85% [11]. Together,

these data suggest that HT may be less ef fective for VMS after RRSO

compared to natural menopause, at least during the initial months. By

6–12 months HT effectively reduced both the prevalence and severity

of VMS. In non-HT users (40%) the severity of VMS was consistent be-

tween 3 and 12 months. In WHAM the dose of estrogen in HT was not

standardized but most RRSO participants (66.7%) were taking estradiol

doses of 50–75 μg/day (data not shown). The optimal dose and duration

of estrogen following early menopause is uncertain [28]. In women with

spontaneous premature ovarian insufﬁciency the general population

higher doses of estrogen (up to 100 μg/day) are recommended [29]. In

this study it is possible that higher doses of estroge n may have been

more effective for VMS. However, we found no association between es-

trogen dose and prevalence or VMS bother (data not shown). In addi-

tion, the safety of high dose estrogen (and progestin) in women at

elevated risk of breast cancer is uncertain. Women considering HT

after RRSO should be aware that it may not fully resolve their VMS, par-

ticularly night sweats.

Menopause-related QoL was reduced after RRSO reﬂecting changes

in vasomotor, physical and sexual domains. Our ﬁndings differ from

previous studies demonstrating that RRSO does not lead to worse QoL

compared with ovarian cancer screening [25]. However, this study in-

cluded many women who were already peri- or post-menopausal at

baseline and may not reﬂect the true impact of premenopausal oopho-

rectomy on QoL. Similar to the effects on VMS, use of HT did not restore

sexual or physical domains of the MENQOL-I to baseline levels. Women

considering RRSO should be aware of the potential for persistent ad-

verse effects on QoL, particularly sexual and physical symptoms, and

that HT may mitigate but not restore symptoms to pre-operative levels.

More information is needed about the optimal type, dose and duration

of HT in this population.

The MENQOL-I includes psychologic al symptoms which did not

change following RRSO or with HT use. Our

ﬁndings suggest that psy-

chological symptoms such as “dissatisfaction with my personal life”

and “feelings of wanting to be alone” are not menopausal symptoms.

12.1

5.3

24.2

20.2

9.1

56.2

18.2

47.2

11.2

55.4

22.5

47.8

12.2

57.3

25.5

48.3

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

Comparison RRSO Comparison RRSO

Hot Flashes Night Sweats

Percent

Baseline 3m 6m 12m

Fig. 2. Prevalence (%) of hot ﬂashes and night sweats from baseline to 12 months in the RRSO and comparison groups.

Note. Prevalence of vasomotor symptoms was determined by answers of “no” or “yes” on the hot ﬂashes and night sweats questions of the intervention version of the Menopause-Speciﬁc

Quality of Life (MENQOL-I) questionnaire.

0.00

0.50

1.00

1.50

2.00

2.50

3.00

3.50

4.00

Baseline 3m 6m 12m

Mean score

Study time point

Comparison Comp ULCI Comp LLCI

RRSO RRSO ULCI RRSO LLCI

Fig. 3. Degree of bother (mean, 95% conﬁdence interval) from vasomotor symptoms in

RRSO and comparison groups.

Note. Bother is measured by th e vasomotor domain of the intervention version of the

Menopause-Speciﬁc Quality of Life (MENQOL-I) questionnaire. ULCI: Upper limit for the

95% conﬁdence interval; LLCI: Lower limit for the 95% conﬁdence interval.

M. Hickey, K.M. Moss, E.O. Krejany et al. Gynecologic Oncology xxx (xxxx) xxx

Including these symptoms in menopause scales may artiﬁcially inﬂate

the apparent symptom burden of menopause with potential negative

consequences for women [30].

Strengths of the WHAM study include the relatively large sample size,

inclusion of a premenopausal comparison group of a similar age who

retained their ovaries, use of validated measures and the prospective

study design. Limitations include use of hormonal contraception at base-

line, but this was not associated with vasomotor or QoL outcomes after

RRSO. Vasomotor symptoms were not measured until 3 months which

may have missed more severe symptoms immediately after RRSO. We

did not measure cancer worry and this may have affected quality of life.

The study was not randomized and women with more severe VMS may

have been more likely to use HT. Also, the estrogen dose in HT was not

standardized and may have been too low for the effective management

of VMS. Obesity has been associated with more frequent VMS [31]. More

women in the RRSO group were obese (28%) compared to the comparison

group(17%)whichmayhaveaffectedourﬁndings. Most participants were

white and our ﬁndings may not be generalizable to other races [32].

Women considering RRSO want to know what symptoms to expect

and how best to manage them [13]. Our ﬁndings suggest that VMS in-

crease and QoL worsens for some women after RRSO, and that HT im-

proves these symptoms but not to pre-oophorectomy levels. However,

in most cases (86%) bother due to VMS was categorized as “mild” sug-

gesting that severe VMS are not inevitable in this population. There is

an unmet need for consensus guidance on managing women following

RRSO [33–35]. These ﬁndings will inform evidence-based clinical guid-

ance for this population.

Declaration of Competing Interest

MH is an editor for the Cochrane Gynaecology and Fertility Group

Editorial Board and has received pharmaceutical funding from QUE On-

cology P/L, Madorra P/L and Ovoca Bio (Australia) P/L for clinical re-

search outside of the submitted work. CDW has received sponsorship

and honoraria from Biogen and Seqirus and is the Deputy Chair (Honorary)

of VCS Foundation P/L. SMD has received personal fees from AstraZeneca

outside of the submitted work. KMM, EOK, AB, JK, HLS, TT-B, AT and

GDM have no competing interests to declare.

Acknowledgements

This study was supported by Register4 through its members' partic-

ipation in research and/or provision of samples and information

(register4.org.au).

In Australia this study was supported by public funding provided by

the National Health and Medical Research Council of Australia (NHMRC;

Grant # APP1048023), and by philanthropic funding provided by The

Royal Women's Hospital (Melbourne, Australia), The Women's Founda-

tion (Melbourne, Australia), Australia New Zealand Gynaecological On-

cology Group (ANZGOG, Sydney, Australia) and the Westmead Hospital

Familial Cancer Service (Sydney, Australia). In the USA this study was

supported by philanthropic funding provided by the Basser Centre for

BRCA and the Susan G. Komen organization (Grant # SAC150003). None

of the funding agencies had a role in the design or conduct of the study,

nor the collection, management, analyses or interpretation of the data,

nor the preparation or approval of this manuscript.

MH is supported by a NHMRC Practitioner Fellowship (ID #

1058935). SMD is supported by the Komen Foundation for the Cure.

12.1

5.4

5.3

24.2

21.6

19.3

9.1

80.6

39.6

18.2

55.6

41.5

11.2

85.7

36.8

22.5

68.6

35.1

12.2

85.3

40.0

25.5

58.8

41.8

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

80.0

90.0

100.0

Comparison No HT Had HT Comparison No HT Had HT

Hot Flashes Night Sweats

Percent

Baseline 3m 6m 12m

Fig. 4. Prevalence (%) of hot ﬂashes and night sweats from baseline to 12 months by HT use in RRSO participants.

Note. Prevalence of vasomotor symptoms was determined by answers of “no” or “yes” on the hot ﬂashes and night sweats questions of the intervention version of the Menopause-Speciﬁc

Quality of Life (MENQOL-I) questionnaire.

0.00

0.50

1.00

1.50

2.00

2.50

3.00

3.50

4.00

4.50

Baseline 3m 6m 12m

Mean score

Study time point

Mean vasomotor bother by HT use (MENQOL)

Comparison Comp ULCI Comp LLCI

No HT No HT ULCI No HT LLCI

Had HT Had HT ULCI Had HT LLCI

Fig. 5. Degree of bother (mean, 95% conﬁdence interval) from vasomotor symptoms by HT

use in RRSO participants.

Note. Bother is measured by th e vasomotor domain of the intervention version of the

Menopause-Speciﬁc Quality of Life (MENQOL-I) questionnaire. ULCI: Upper limit for the

95% conﬁdence interval; LLCI: Lower limit for the 95% conﬁdence interval.

M. Hickey, K.M. Moss, E.O. Krejany et al. Gynecologic Oncology xxx (xxxx) xxx

GDM is support ed by a NHMRC Principal Research Fellowship (ID #

APP1121844).

We are grateful to the women who generously gave of their time to

participate in this study and to the following people who assisted with

participant recruitment and study management: Lesley Andrews and

Leon Botes (Prince of Wales Hospital, Sydney, Australia), Bettina Meiser

(University of New South Wales, Sydney, Australia), Mariana De Sousa

(University of Technology Sydney, Australia), Orla McNally and Debo-

rah Neesham (The Royal Women's Hospital, Melbourne, Au stralia),

Sue Shan ley, Gill ian Mitchell and Mary Shanahan (Peter MacCallum

Cancer Centre, Melbourne, Australia), Masako Dunn (Chris O'Brien

Lifehouse, Sydney, Australia), L. Jane McNeilage a nd Marion Harris

(Monash Medical Centre, Melbourne, Australia), Geoffrey L indeman

(The Royal Melbourne Hospital, Australia), Peter Grant (Mercy Hospital

for Women, Melbourne, Australia) and Nipuni Gamage (The University

of Melbourne, Australia). Thanks also to Mary-Ann Davey (Monash Uni-

versity, Melbourne, Australia) and Sabine Braat (The University of Mel-

bourne, Australia) for the provision of preliminary advice and support

with statistical methodology and analysis.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.

org/10.1016/j.ygyno.2021.07.029.

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