Care after premenopausal risk‐reducing salpingo‐oophorectomy in high‐risk women: Scoping review and international consensus recommendations

Women at high inherited risk of ovarian cancer are offered risk‐reducing salpingo‐oophorectomy (RRSO) from age 35 to 45 years. Although potentially life‐saving, RRSO may induce symptoms that negatively affect quality of life and impair long‐term health. Clinical care following RRSO is often suboptimal. This scoping review describes how RRSO affects short‐ and long‐term health and provides evidence‐based international consensus recommendations for care from preoperative counselling to long‐term disease prevention. This includes the efficacy and safety of hormonal and non‐hormonal treatments for vasomotor symptoms, sleep disturbance and sexual dysfunction and effective approaches to prevent bone and cardiovascular disease.


| I N TRODUC TION
Carriers of germline pathogenic variants (PVs) in BRCA1 and BRCA2 have an approximately 44% and 17% lifetime risk of ovarian cancer or fallopian tube cancer (referred to as ovarian cancer hereafter) and a 72% and 69% lifetime risk of breast cancer. 1 Surgical removal of both ovaries and fallopian tubes (risk-reducing salpingo-oophorectomy [RRSO]), reduces the risk of ovarian cancer by 80-95% and reduces all-cause mortality in BRCA1/2 PV carriers. 2,3The National Comprehensive Cancer Network (NCCN) recommends that women with BRCA1 PVs undergo RRSO between 35 and 40 years of age, those with BRCA2 PVs between 40 and 45 years, and those with BRIP1, RAD51C and RAD51D between 45 and 50 years. 4NCCN recommends that timing of hysterectomy ± RRSO for Lynch syndrome be individualised, as risk varies by PV. 5 However, patient concerns about the effects of surgical menopause after RRSO are a barrier to risk-reducing oophorectomy. 6][9][10][11][12] Prospective studies show that bone density is reduced 2 years after RRSO, which is only partially mitigated by hormone replacement therapy (HRT). 13Similarly, HRT decreases but does not fully resolve vasomotor symptoms or sexual dysfunction after RRSO. 8In addition, those with a personal history of breast cancer are advised against taking HRT. 14,15Effective non-hormonal options are available, but may not be routinely offered.The purpose of this scoping review is to provide clinical recommendations for menopausal symptom management and the prevention of long-term adverse outcomes following RRSO (Table 1).These recommendations were voted on using a modified Delphi questionnaire by a panel of 27 international experts in 12 countries across eight disciplines to form the consensus.

| M ET HODS
We searched PubMed database for English-language studies published from inception to January 2021 using a scoping review process (search terms are reported in eAppendix in Data S1).Two reviewers (MH, DRN) independently screened 6705 publications first by titles and abstracts, and then 297 full-text articles from which 65 publications were included (Figure 1).Characteristics of these 65 including design and country of origin are summarised in Table 2. Most were from North America (35; 46%), followed by multicontinental collaborations (24; 32%) and Europe (10; 13%).Most were cohort studies (21; 28%), followed by randomised controlled trials (RCTs) (13; 17%) and systematic reviews (11; 15%).

| Scoping review
Scoping reviews are recommended for interrogating and summarising the literature when there is more than one research question.The main difference between a scoping review and a systematic review is that systematic reviews address one particular question, whereas a scoping review addresses several questions from a large and diverse body of literature pertaining to a broad topic.Hence, a scoping review (rather than a systematic review) was the most rigorous approach to evaluate the evidence and inform these clinical recommendations.This scoping review included 6705 published papers, which formed the basis of these consensus recommendations.We have followed the preferred framework for a scoping review: (1) identifying the research question, (2) identifying relevant studies, (3) study selection, (4) charting the data, (5) collating, summarising and reporting the results, and (6) an optional consultation exercise. 16As recommended, the clinical recommendations have been graded based on the level of evidence they were derived from.

| Consensus process
Two authors (MH and DRN) contacted the first and/or senior authors from 65 publications identified in the scoping review that reported short-or long-term health outcomes following RRSO or care of high-risk women following RRSO to invite them to contribute to the consensus process.Of these, 27/29 responded and agreed to participate.The authors represent eight disciplines involved in the care of PV carriers such as BRCA1/BRCA2 from 12 countries.Consensus was achieved using an online modified Delphi Survey including 50 proposed recommendations based on data synthesised from the scoping review, with grading of the evidence using traditional Ia-IV ratings, shown in Table 1.For each question they were asked to rate their responses on a Likert scale from 1 to 9. Statements were Strongly Recommend (SR) when more than 80% of participants scored as '7-9' and less than 10% scored as '1-3', Recommended (R) when more than 70% scored as '7-9' and less than 15% scored as '1-3', and Not Recommended (NR) when more than 70% scored as '1-3' and less than 15% scored '7-9'.Neutral statements (N) did not meet any of these criteria.Twenty-two consensus statements were scored as (SR), 8 were (R) and 21 were (N).None were classed as (NR).Clinically relevant consensus recommendations are listed in Table 1.Most of the consensus process occurred during the pandemic and formal meetings between the authors were not possible.Communications were primarily by email and online surveys.Virtual meetings were held as needed.

| Search strategy and selection criteria
We

| PR EOPER ATI V E COU NSE L LI NG OF HIGH-R ISK WOM E N BEFOR E R R SO
Common concerns for women facing RRSO include loss of fertility, management of menopausal symptoms, impact on sexual function and long-term health. 6It was strongly recommended by the panel that these issues be discussed before RRSO to ensure informed consent, set realistic expectations and generate an individualised plan for postoperative care.High-risk women making decisions about surgery to reduce their risk of ovarian cancer may benefit from a Decision Aid, and patient information resources addressing the consequences and management of surgical menopause after RRSO are available to download. 17,18eferral to a fertility specialist should be offered where relevant.
• Offer women who have not completed childbearing referral to a fertility specialist-SR • Address patient concerns about loss of fertility, menopausal symptoms, sexual function and long-term health 6 -SR

| Discussion of concurrent hysterectomy at RRSO
Hysterectomy is advised for women with Lynch syndrome where endometrial cancer risk is significantly elevated and the efficacy of screening is uncertain. 5,19Decision-making about hysterectomy at the time of RRSO for BRCA1 and BRCA2 is more complex.Two systematic reviews and meta-analyses on endometrial cancer risk in BRCA1 and BRCA2 carriers show a slight increased relative risk of serous endometrial cancer in BRCA1 (Standardised Incidence Ratio 2.81) and BRCA2 (Standardised Incidence Ratio 1.75) 20,21 but minimal increase in absolute risk.However, a recent (2022) study of 5341 families with PVs in BRCA1 and BRCA2 shows no increased risk of endometrial cancer. 22In light of these findings, NCCN guidelines advise discussion of the benefits and risk of hysterectomy but do not recommend routine hysterectomy in BRCA PV carriers.

| COU NSE L LI NG A N D CA R E OF HIGH-R ISK WOM E N A F TER R R SO
The overall aim after RRSO is prevention of adverse health consequences from early surgical menopause and optimisation of long-term physical and emotional health.

| M A NAGE M E N T OF VASOMOTOR SY M P TOMS FOL LOW I NG R R SO I N WOM E N W ITHOU T BR E AST CA NCER
Around 80% of premenopausal women develop vasomotor symptoms after RRSO. 8Cross-sectional studies report more severe vasomotor symptoms after RRSO compared with natural menopause, which may be persistent. 23HRT may be less effective for vasomotor symptoms after RRSO.In the general population, HRT reduces vasomotor symptoms by around 80%, but following RRSO around 40% report persistent symptoms despite HRT use. 8Uptake of HRT after RRSO varies widely across the country ranging from 5% to 75%, but on average 50-60% of women take HRT after RRSO. 24he long-term safety of HRT for breast cancer in this population is not known.A prospective study of 872 BRCA1 PV carriers of whom 43% (77% premenopausal, 23% postmenopausal at RRSO, mean age 43 years, range 30-70 years) took HRT for a mean of 3.9 years (range 0.5-19 years) concluded that estrogen alone did not increase breast cancer risk but the safety of progestin-containing HRT was uncertain. 25 2019 systematic review including seven studies (n = 933 BRCA1/2 PV carriers) concluded that HRT could be used for up to 4.3 years without increasing breast cancer risk.26 Age at initiation of HRT may be important.A retrospective study of 306 BRCA1/2 PV carriers followed up for up to 7.26 years after RRSO found no overall increased risk of breast cancer after 4 years of HRT; however, those who started HRT after age 45 years had a more than three-fold increased risk of breast cancer (odds ratio 3.43, p < 0.05, 95% CI 1.2-9.8).27 Whether this reflects higher risk of BC with age or is a direct effect of HRT is unknown.This information should be balanced with the potential cardioprotective effects of HRT if taken until the age of 50 years, after early oophorectomy.28 Together, these data support offering HRT to women under age 45 years with duration of use dependent on previous mastectomy and/or hysterectomy, patient wishes, severity of menopausal symptoms and risk factors for osteoporosis.However, more information is needed about morbidity and mortality associated with HRT use in high-risk women and little is known about safety beyond 4-5 years of use.
If progestin is needed, limited observational data in the general population suggest that micronised progesterone might have a lower risk of breast cancer compared with synthetic progestins, but there are no studies in BRCA1/2 PV carriers. 29Intrauterine progestin via the levonorgestrel intrauterine system has minimal systemic absorption but is still associated with elevated breast cancer risk (relative risk 1.19, 95% CI 1.13-1.25) in the general population. 30Data from the general population suggest that those with risk factors for venous thromboembolism should be offered transdermal rather than oral estrogen. 31Offer HRT following RRSO below age 45 years for vasomotor symptoms and/or disease prevention 25,26 -SR • After age 45 years, individualise HRT considering need for progestin, previous risk reducing mastectomy, severity of symptoms, and risk factors for osteoporosis-SR • Offer transdermal HRT in those at elevated risk of venous thromboembolism 31 -R • Consider micronised progesterone instead of synthetic progestogen 29 -N

| A NAGE M E N T OF VASOMOTOR SY M P TOMS FOL LOW I NG R R SO I N WOM E N W ITH BR E AST CA NCER
A 2021 systematic review and meta-analysis in the general population (n = 4050) showed a two-to three-fold increased risk of recurrent or new breast cancer in HRT users after estrogen receptor-positive but not estrogen receptor-negative breast cancer. 32When HRT is contraindicated or avoided there are several effective non-pharmacological and nonhormonal treatments for vasomotor symptoms. 33,341 | Non-pharmacological treatments for vasomotor symptoms (Figure 2) Randomised controlled trials show that cognitive behavioural therapy (CBT) reduces the bother/impact of vasomotor symptoms in the general population and after breast cancer. 35Following RRSO, mindfulness-based stress reduction improves quality of life for patients with vasomotor symptoms. 36One RCT in the general population showed that clinical hypnosis reduced vasomotor symptoms. 33Some RCTs show that acupuncture reduces vasomotor symptoms after breast cancer, but data are mixed. 33 • Offer CBT for vasomotor symptoms 35,37 -N • Consider mindfulness-based stress reduction 36 -N

| Non-hormonal pharmacological treatments for vasomotor symptoms (Figure 2)
Evidence from RCTs in breast cancer patients demonstrates that effective non-hormonal pharmacological therapies for vasomotor symptoms include selective serotonin reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI), gabapentin, clonidine and oxybutynin, although studies are lacking after RRSO. 33,34No single agent has proven superior to others, but SSRI and SNRI reduce vasomotor symptoms by around 50-60%.A systematic review of non-hormonal treatments for vasomotor symptoms after breast cancer showed similar outcomes for 10/20/30 mg citalopram and 10/20 mg paroxetine, venlafaxine 75 mg daily and gabapentin 900 mg. 38Escitalopram 10/20 mg is also effective. 39Clonidine reduces vasomotor symptoms by about 40%. 33,34Oxybutynin 2.5-5 mg twice a day is also effective, although adverse effects may limit its use. 33There is a hypothetical risk that fluoxetine and paroxetine may interfere with tamoxifen metabolism but this does not appear to impact on breast cancer outcomes. 40 • Offer SSRI (paroxetine 10/20 mg; citalopram 10/20/30 mg; escitalopram 10/20 mg) or SNRI (venlafaxine 75 mg controlled release or desvenlafaxine 100 mg) 38,39 -N • Offer gabapentin 300-900 mg at night for vasomotor symptoms that disturb sleep 38 -N • Consider clonidine 0.1-mg patch 33,34 -N • Consider oxybutynin 2.5-5 mg twice a day 33 -N • Consider hypnosis or acupuncture 33 -N

| SL E E P DIST U R BA NC E A F TER R R SO
Sleep disturbance is common over the menopause transition and may be independent of vasomotor symptoms.A retrospective study in the general population suggested that sleep quality was worse after surgical menopause compared with natural menopause. 41In a prospective study, following RRSO, HRT improved sleep quality but not to baseline levels. 9Sleep disturbance may increase the risk of mood disturbance at menopause and requires active management.High-level evidence in the general population supports the efficacy of CBT for insomnia (CBT-I). 42Care should include advice about sleep hygiene including avoidance of caffeine and alcohol, reducing noise, routine exercise and maintaining a regular sleep schedule. 43Following breast cancer, both gabapentin and acupuncture improve sleep. 44The addition of zolpidem 5-10 mg to SSRI improves sleep and quality of life after breast cancer. 45One RCT in breast cancer survivors showed that melatonin 3 mg improves subjective sleep quality without significant adverse effects. 46Advise about good sleep hygiene including avoidance of caffeine and alcohol, eliminate noise from bedroom, get routine exercise and maintain a regular sleep schedule 43 -R • Offer CBT Insomnia programmes available on-line 42 -N • Offer HRT to eligible women with sleep disturbance due to vasomotor symptoms 9 -SR • Consider gabapentin 300-900 mg at night to improve sleep quality and duration 44 -N • Consider augmentation of SSRI and SNRI with zolpidem 5-10 mg 45 -N • Consider melatonin 3 mg 46 -N

| MOOD DIST U R BA NCE A F TER R R SO
Women with previous major depressive disorder are at risk of relapse over the menopause transition. 47,48Other risk factors for depression include anxiety, stressful life events, vasomotor symptoms and poor sleep. 48HRT does not prevent or treat depression over the menopause transition.However, CBT as shown in general population women, reduces depressive symptoms and improves sleep. 37Consensus guidelines for the general population indicate that mood disturbances should be managed with standard approaches such as antidepressants and/or psychotherapy and refer if indicated. 48Be aware that previous depressive illness increases risk of recurrent depression 47 -SR • Consider CBT for with vasomotor and depressive symptoms 37 -R • Consider SSRI/SNRI for vasomotor symptoms and depressive symptoms-N • Refer for major depressive disorder or anxiety disorder-SR

| SE X UA L DYSF U NC TION A F TER R R SO
Several cross-sectional studies report a high prevalence of sexual dysfunction after RRSO, which may be worse after breast cancer or treatment with endocrine therapy. 7,49Sexual problems after RRSO include vaginal dryness and dyspareunia, reduced libido, reduced arousal and difficulty with orgasm.Preoperative counselling about sexual function may reduce subsequent distress after RRSO. 50Risk factors for sexual dysfunction in BRCA PV carriers after RRSO include depression, vasomotor symptoms, poor sleep and sexual inactivity. 51RT improves but does not resolve sexual dysfunction after RRSO. 11,12SSRI and SNRI may cause sexual adverse effects, including difficulty reaching orgasm or hypoactive sexual desire disorder (HSDD).In the general population, a 2014 systematic review reported that vaginal estrogens effectively relieve common genito-urinary symptoms associated with menopause. 52A systematic review in 2020 of vaginal estrogen safety reported that these products appear safe for at least 1 year of use. 53Although vaginal estrogens are systemically absorbed, circulating concentrations remain in the postmenopausal range. 53In the general population, long-term followup studies do not show any increase in breast or endometrial cancer with vaginal estrogen use. 54Although the safety and efficacy of vaginal estrogen in BRCA1/2 pathogenic variant carriers has not been studied, high rates of sexual dysfunction in this population suggest that vaginal estrogens should be considered for troublesome genitourinary symptoms such as vaginal dryness in those without a personal history of breast cancer. 49After estrogen-dependent breast cancer, American College of Obstetricians and Gynecologists guidelines advise using non-hormonal methods as first line for genitourinary symptoms, but to consider vaginal estrogen if these are ineffective, following discussing with the treating oncologist. 55n the general population, vaginal dehydroepiandrosterone (DHEA; prasterone) improves vaginal atrophy, sexual satisfaction and dyspareunia without increasing circulating estradiol or testosterone. 56The North American Menopause Society Global position statement advises assessment for HSDD using the Decreased Sexual Desire Screener. 57Topical testosterone is recommended for HSDD in the general population, but no studies have evaluated its safety in BRCA1/2 carriers. 58,59libanserin and bremelanotide are US Food and Drug Administration (FDA) approved non-hormonal therapies for HSDD in premenopausal women and have similar efficacy and use in postmenopausal women, and can be considered. 60,61In one study after RRSO, an education session including sexual health, relaxation training, body awareness and CBT improved overall sexual functioning. 62Before RRSO, discuss the potential detrimental effects on sexual function which may be long-lasting and not restored by HRT 11,12 -SR • Ask about sexual activity and satisfaction after RRSO-SR • Review risk factors for sexual dysfunction such as depression, vasomotor symptoms, poor sleep and sexual inactivity 51 -SR • If HSDD, consider topical testosterone therapy 58 -N • Since in many countries female testosterone products do not exist, use one-tenth of a male FDA-approved product (best in tube form) 59 -N • Do not use testosterone compounded or pellets 58 -R • Consider vaginal prasterone (DHEA) for vaginal atrophy and dyspareunia 56 -N

| GE N ITOU R I NA RY SY M P TOMS A F TER R R SO
Around 50% of postmenopausal women report genitourinary symptoms, which may include dryness, dyspareunia, urinary urgency/frequency, and vulvar and vaginal burning.A systematic review of 53 RCTs in the general population showed that vaginal estrogen improves vaginal dryness and may also prevent recurrent urinary tract infection. 63,64ffective non-hormonal therapies include hyaluronic acid containing moisturisers and lubricants but these may not be as effective as estrogen. 65After breast cancer, US guidelines advise that vaginal estrogen be considered if non-hormonal therapies are ineffective, in consultation with the medical oncologist. 55Vaginal prasterone and oral ospemifene are also effective but not licenced after breast cancer. 56A shamcontrolled RCT of vaginal CO 2 laser in the general population showed no benefit for any genitourinary symptoms including dyspareunia. 66Another RCT reported that 4% aqueous lidocaine before penetrative intercourse allowed 17/20 (85%) breast cancer survivors who previously abstained from intercourse to resume sexual activity. 67 • Consider non-hormonal treatments including hyaluronic acid containing vaginal moisturisers and lubricants 33,65 -SR • Offer vaginal estrogen for vaginal dryness 63 -SR • Discuss vaginal estrogen with oncologist if previous breast cancer 55 -R • Consider topical 4% lidocaine for dyspareunia in breast cancer survivors 67 -N • Do not offer vaginal laser 66 -N

| CA R DIOVASCU L A R H E A LTH A F TER R R SO
Cardiovascular disease (CVD) is the leading cause of death in men and women worldwide.BRCA1/2 PV carriers may be at higher risk of CVD as the result of early menopause, chest radiotherapy or chemotherapy for breast cancer. 68Surgical menopause may further increase risk.Pooled data from 203 767 women in the general population reported a higher risk of CVD following surgical menopause compared with women of similar age with spontaneous early menopause, with greater risk in younger age at oophorectomy. 69se of HRT until age 50 years reduced CVD risk. 69In the Nurse's Health Study, a prospective cohort study of 30 000 women undergoing hysterectomy for benign disease, bilateral oophorectomy was associated with increased mortality in women aged younger than 50 years who did not take estrogen therapy. 28A cross-sectional study of 165 BRCA1/2 PV carriers, 5-24 years after RRSO (at <45 years) showed no evidence of increased CVD. 11Sedentary behaviour and physical inactivity are the leading modifiable risk factors for CVD worldwide. 70,71Other modifiable risk factors include obesity, smoking, hypertension, elevated lipids and diabetes.The cardioprotective effects of regular physical activity in the general population are clear and extend across all ages, sex and race. 71Evidence-based guidelines from the general population to optimise CV health should be applied to the BRCA1/2 population.According to the Physical Activity Guidelines of the US Department of Health and Human Services, adults should reduce sedentary activity and aim for moderate aerobic exercise of 150-300 minutes/week, or vigorous aerobic exercise of 75-150 minutes/week and strength training 2 days per week to improve overall health and reduce risk of CVD.

| BON E H E A LTH A F TER R R SO
In the general population, premature ovarian insufficiency reduces bone mineral density and may increase fracture risk. 72Use of HRT may prevent or minimise bone loss. 72A retrospective chart review (n = 225) following RRSO demonstrated that 56% had osteopenia and 12% had osteoporosis. 73nother retrospective cohort study after RRSO suggested that HRT users had higher bone density than non-users. 74rospective studies after RRSO suggest that HRT improves bone density and strength but not to baseline levels. 13,75The optimal dose and delivery system of HRT to prevent osteoporosis and fracture is not known.The 2020 update of the American Association of Clinical Endocrinologists clinical practice guidelines on osteoporosis considers early menopause to be an indication for baseline bone mineral density with dual-energy X-ray absorptiometry (DXA) testing within the first year with repeat 1-2 years later. 76Endocrinology referral should be considered for significant osteopenia, osteoporosis or for women at risk of minimal trauma fracture. 76If baseline DXA shows mild osteopenia, repeat every 2 years thereafter or if normal, a repeat study should be considered in 3-5 years or based on healthcare system reimbursement.If bone mineral density remains normal until age 50 years, consider stopping DXA and resume at age 65 years according to general population guidelines.The Fracture Risk Assessment Tool (FRAX) can be used to calculate 10-year fracture risk. 76Modifiable risk factors for osteoporosis include low body mass index (<18 kg/ m 2 ), low physical activity, insufficient calcium and vitamin D intake, insufficient protein intake, smoking, and excessive consumption of alcohol (>2 drinks/day).Management to detect and prevent osteoporosis include monitoring bone mineral density and aiming for normal vitamin D levels (>30 ng/mL; 75 nmol/L) with adequate vitamin D intake (600-800 IU/day) 76,77 and adequate calcium intake (1000-1200 mg/day) along with limiting caffeine and alcohol and smoking cessation.Bone strengthening and fall prevention include maintaining an active lifestyle including routine aerobic, weight-bearing (3-5×/week), balance and musclestrengthening (2-3×/week) exercises. 76,77Offer HRT to those without contraindications 13  on FRAX • Osteopenia +10-year major osteoporosis-related fracture risk of more than 20% on FRAX A N D R R SO It is not known whether surgical menopause affects cognition.A systematic review of 11 studies (n = 18 867 women) in the general population found conflicting results from low-quality studies and concluded that surgical menopause before age 45 years may increase dementia and cognitive decline. 78Following RRSO, one small cross-sectional study reported a small subjective but not objective decline in cognition at 6 months that was not prevented by HRT.79 More information from prospective studies of cognition after RRSO is needed.Recommendations for the prevention of dementia and effects of HRT are unanswered.

| U NCERTA I N TIE S
There are numerous areas of uncertainty around RRSO in BRCA1/2 pathogenic variant carriers.After RRSO, the optimal dose, route of administration and duration of HRT use are unknown.Similarly, it is uncertain whether HRT can be safely used by women with a personal history of estrogen receptor-negative breast cancer who have undergone bilateral mastectomy.The views of high-risk women were not formally sought in this consensus process which is a limitation.How best to optimise long-term health and mitigate the risk of chronic disease after RRSO requires long-term prospective studies.

| CONCLUSIONS
Despite the efficacy of premenopausal RRSO for reducing ovarian cancer risk and improving mortality in high-risk women, many women experience troublesome menopausal symptoms and oophorectomy may have adverse implications for long-term health.Our panel of international experts has developed evidence-based recommendations for managing vasomotor, sleep, mood, sexual, and genitourinary symptoms and optimising bone and cardiovascular long-term health.Emerging evidence suggests that HRT reduces but does not eliminate the adverse effects of premenopausal oophorectomy.Women and clinicians considering RRSO should be aware of these risks and clinical care should focus on available safe options for symptom management and optimisation of long-term health.

C ON F L IC T OF I N T E R E S T S TAT E M E N T
None declared.

DATA AVA I L A BI L I T Y S TAT E M E N T
Data openly available in a public repository that issues datasets with DOIs.The data that support the findings of this study are openly available in [https://pubmed.ncbi.nlm.nih.gov/].

E T H IC S A PPROVA L
Ethics approval was not required for this consensus statement.
MH and DRN conceived and designed this paper, performed the scoping review, wrote the initial draft and were responsible for revising this draft based on comments from the other authors.SMD, JK, JAH, EJC and VSP made substantial contributions to the conception or design of the work and drafting of the work.VSP, TG, SR, SLB and SAK contributed to the acquisition, analysis and made substantial contributions to the interpretation of data for the work.All authors except TG and SLB participated in the modified Delphi questionnaire.DRN, SMD, JK, JAH, EJC, VSP, MBZ, BMN, TG, SR, AWK, HJP, NY, RM-C, SLB, ALSF, NJ, FG, DGE, UM, SAK, CBP, GG, CM, MJ, DJB and MH made contributions to revising it critically for important intellectual content and gave final approval of the version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.AC K NOW L E D GE M E N T SOpen access publishing facilitated by The University of Melbourne, as part of the Wiley -The University of Melbourne agreement via the Council of Australian University Librarians.F U N DI NG I N FOR M AT ION Care after premenopausal risk reducing salpingo-oophorectomy in high risk women: international consensus recommendations.
T A B L E 1Management of VMS following RRSO in women with breast cancer Offer non-hormonal treatments for troublesome VMS-Figure2Management of sleep disturbance after RRSO Advise about good sleep hygiene including avoidance of caffeine and alcohol, eliminate noise from bedroom, get routine exercise and maintain a regular sleep schedule

premature References Level of evidence Rec
• Previous hip, fragility or clinical vertebral fracture • DXA femoral neck, total hip or spine T score less than −2.5 (osteoporosis)• osteopenia +10-year hip fracture risk of more than 3% on FRAX• osteopenia +10-year major osteoporosis-related fracture risk of more than 20% on FRAXT A B L E 1 (Continued)ovarian insufficiency', 'early menopause', 'surgical menopause', 'hormone replacement therapy', 'menopausal hormone therapy', 'genitourinary' and 'non-cancer endpoints' restricted to articles in English.Duplicate articles from the database search were removed using Endnote (Endnote 18, Clarivate™), and uploaded to Covidence (Covidence) for screening (Appendix in Data S1). 14 Study design and country of origin.
F I G U R E 1 Articles identified and screened for final eligibility.T A B L E 2Abbreviations: A, Asia; AU, Australasia; BC, breast cancer; CV, cardiovascular health; EU, Europe; GU, genitourinary; Mx, management; NA, North America; RCT, randomised controlled trial; SA, South America; SR, systematic reviews, (%).*Multinational collaboration. 70 MH is funded by a National Health and Medical Research Council (NHMRC) Investigator Grant.DJB is funded by Science Foundation Ireland Precision Oncology Ireland grant 18/SPP/3522 and the Irish Cancer Society Women's Health Initiative.EJC is supported by a National Institute for Health and Care Research (NIHR) Advanced Fellowship (NIHR300650) and the NIH Manchester Biomedical Research Centre (1S-BRC-1215-20007).CBP is funded by a private donation from Stephen Gomez.No other authors have relevant financial disclosures.