Clinical trial NCT03835793: Health After eaRly Menopause Due to Oophorectomy
Official title: Favourable and Unfavourable Health Effects of Risk-Reducing Salpingo-Oophorectomy in Women With a High Genetic Risk of Ovarian Cancer
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Surgical Menopause
BRCA1 Mutation
BRCA2 Mutation
Cardiovascular Diseases
Bone Mineral Density
Cognitive Decline
Quality of Life
Menopause Surgical
Keywords: long-term
premature ovarian insufficiency
Lead sponsor: The Netherlands Cancer Institute
Sponsor class: OTHER
Collaborators: name: Dutch Cancer Society
name: Erasmus Medical Center
name: Radboud University Medical Center
First posted: 2019-02-11
Enrollment: 750
Sex: FEMALE
Minimum age (years): 55
Standard ages: ADULT
OLDER_ADULT
Observational model: COHORT
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Women are eligible if they underwent RRSO before age 45 and the RRSO was done 10 or more years ago (early RRSO group) and women are eligible as control group if they did not undergo RRSO, or underwent RRSO after age 55 while reaching natural menopause after the age of 50 years. The comparison group will be frequency-matched with the RRSO group on categories of calendar year of birth, and breast cancer history. For each patient with breast cancer, the investigators will perform individual matching accounting for age at breast cancer diagnosis and carrier status. For the early RRSO group the investigators select women who underwent RRSO at least 10 years ago and are currently older than 55 years because the investigators expect subclinical atherosclerosis not to manifest earlier.

Brief summary: Risk-Reducing Salpingo-Oophorectomy (RRSO) at the age of 35 to 45 years is recommended for women with a high genetic risk for ovarian cancer. While this procedure decreases the risk of ovarian cancer by 80-96%, it also results in an immediate menopause. Current research on potential adverse effects of premenopausal risk-reducing salpingo-oophorectomy, such as increased risk of cardiovascular disease, compromised bone health, cognitive dysfunction and reduced quality of life, is limited, mostly due to short follow up.

The investigators will conduct a multicenter cross-sectional study nested in a cohort of BRCA mutation carriers from 8 Dutch centers for hereditary cancer. Eligible participants are women who underwent RRSO before the age of 45. The participants will be frequency-matched on current age with women above the age of 55 without RRSO or with RRSO after the age of 55. Participants will complete an online questionnaire containing various questions about lifestyle, medical history, risk factors for cardiovascular disease, bone health, cognition and quality of life. Participants will be asked to visit one of the participating hospitals for a blood test, a cardiovascular assessment and a DEXA scan for determining bone mineral density. Afterwards participants will be requested to perform the online Amsterdam Cognition Scale.

Detailed description: Rationale: Women at high genetic risk of ovarian cancer are advised to undergo risk-reducing salpingo-oophorectomy (RRSO) at ages 35-45 years. Currently, in the Netherlands \~500 women/ year opt for RRSO, which minimizes ovarian cancer risk and may decrease breast cancer (BC) risk as well, due to reduced gonadal hormone levels. Besides favorable effects of RRSO on ovarian cancer and, potentially, BC risk, RRSO induces immediate menopause, which may have unfavorable long-term health consequences. Early menopause has been associated with increased risks of cardiovascular disease (CVD), lower bone mineral density (BMD), cognitive impairment, and decreased quality of life. Current evidence regarding these health effects is mainly based on women with a natural early menopause, and it is unknown whether these results hold for women undergoing RRSO at early premenopausal ages.

Objective: The investigators will investigate long-term health effects of premenopausal RRSO on (subclinical) cardiovascular status, BMD, cognition and quality of life.

Study design: the investigators will assess long-term health effects of RRSO in a cross-sectional study, among 500 women who underwent premenopausal RRSO compared to 250 women of the same age without RRSO (or with RRSO after age 55). Eligible women will be invited to participate in a screening program assessing cardiovascular status, bone mineral density, cognitive functioning and quality of life.

Study population: Women are eligible for the premenopausal RRSO group if:

* RRSO before the age of 45 years;
* RRSO was done 10 or more years ago; Women are eligible for the comparison group without premenopausal RRSO if the participant did not undergo RRSO before the age of 55 years, and did not have a natural or therapy induced menopause before age 50.

Primary study outcome: To study long-term effects of premenopausal RRSO on:

* (subclinical) CVD
* BMD
* Cognition

Secondary study outcome: To study long-term effects of premenopausal RRSO on:

* Quality of life
* Urogenital problems
* Cardiovascular risk factors

Furthermore, the investigators will examine the influence of age at RRSO, time since RRSO, hormone replacement therapy (HRT), carrier ship of a BRCA1 or BRCA2 mutation and BC history on the outcome.

The obtained knowledge will assist physicians in counselling women with high ovarian cancer risk and help them to make well-informed decisions.

Eligibility criteria: Inclusion Criteria:

* RRSO before age 45
* RRSO after age 55
* no RRSO

Exclusion Criteria:

* metastatic disease
* Premature ovarian insufficiency
* Physical or mental problems interfering with a outpatient visit
* nonbioabsorbable cardiac stent
* insufficient understanding of the Dutch language

Primary outcomes:
measure: What is the prevalence of atherosclerotic diseases in women with RRSO compared to women with a high genetic risk of ovarian cancer with a natural menopause as assessed by coronary artery calcium scoring in agatston units
timeFrame: 4 years
measure: What is the prevalence of atherosclerotic diseases in women with RRSO compared to women with a high genetic risk of ovarian cancer with a natural menopause as assessed by pulse wave velocity in meters/second
timeFrame: 4 years
measure: What is the prevalence of atherosclerotic diseases in women with RRSO compared to women with a high genetic risk of ovarian cancer with a natural menopause as assessed by high-sensitive CRP in miligram/liter
timeFrame: 4 years
measure: What is the prevalence of atherosclerotic diseases in women with RRSO compared to women with a high genetic risk of ovarian cancer with a natural menopause as assessed by high-sensitive cardial Troponine T in microgram/liter
timeFrame: 4 years
measure: What is the prevalence of osteoporosis in women with a premenopausal RRSO compared to women with a high genetic risk of ovarian cancer with a natural menopause as assessed by dual-energy X-ray absoptiometry in T- and Z-scores
timeFrame: 4 years
measure: What is the prevalence of osteoporosis in women with a premenopausal RRSO compared to women with a high genetic risk of ovarian cancer with a natural menopause as assessed by instant vertebral assessment
timeFrame: 4 years
measure: What is the prevalence of osteoporosis in women with a premenopausal RRSO compared to women with a high genenetic risk of ovarian cancer with a natural menopause as assessed by beta-CTX in picogram/mililiter
timeFrame: 4 years
measure: What is the prevalence of osteoporosis in women with a premenopausal RRSO compared to women with a high genenetic risk of ovarian cancer with a natural menopause as assessed by P1NP in miligram/liter
timeFrame: 4 years
measure: What is the prevalence of cognitive decline in women with RRSO compared to women with a natural menopause as assessed by the Amsterdam Cognition Scan
timeFrame: 4 years
Secondary outcomes:
measure: Quality of life after a premenopausal RRSO compared to women from families with a high genetic risk of ovarian cancer with a natural menopause as assessed by validated questionnaires such as the SF-36
timeFrame: 4 years
measure: Quality of life after a premenopausal RRSO compared to women from families with a high genetic risk of ovarian cancer with a natural menopause as assessed by validated questionnaires such as the EORTC-QLQ BR23.
timeFrame: 4 years
measure: Quality of life after a premenopausal RRSO compared to women from families with a high genetic risk of ovarian cancer with a natural menopause as assessed by validated questionnaires such as the FACT-ES
timeFrame: 4 years
measure: What is the prevalence of urogenital problems in women with a RRSO compared to women with a natural menopause as assessed by validated questionnaires such as the SAQ
timeFrame: 4 years
measure: What is the prevalence of urogenital problems in women with a RRSO compared to women with a natural menopause as assessed by validated questionnaires such as the UDI-6
timeFrame: 4 years
measure: What is the prevalence of urogenital problems in women with a RRSO compared to women with a natural menopause as assessed by validated questionnaires such as the IIQ-7
timeFrame: 4 years
measure: What is the prevalence of cardiovascular risk factors in women with RRSO compared to women with a high genetic risk of ovarian cancer as assessed by a questionnaire.
timeFrame: 4 years
Other outcomes:
measure: What is the effect of premenopausal RRSO on risk of (contralateral) breast cancer and breast cancer-specific survival as assessed in a prospective setting within a well established cohort.
timeFrame: 4 years
Locations:
city: Amsterdam
country: Netherlands
facility: Netherlands Cancer Institute - Antoni van Leeuwenhoek
Study officials:
affiliation: NKI-AvL
name: Flora E van Leeuwen, Phd
role: PRINCIPAL_INVESTIGATOR
References:
citation: Terra L, Hooning MJ, Heemskerk-Gerritsen BAM, van Beurden M, Roeters van Lennep JE, van Doorn HC, de Hullu JA, Mom C, van Dorst EBL, Mourits MJE, Slangen BFM, Gaarenstroom KN, Zillikens MC, Leiner T, van der Kolk L, Collee M, Wevers M, Ausems MGEM, van Engelen K, Berger LP, van Asperen CJ, Gomez-Garcia EB, van de Beek I, Rookus MA, Hauptmann M, Bleiker EM, Schagen SB, Aaronson NK, Maas AHEM, van Leeuwen FE. Long-Term Morbidity and Health After Early Menopause Due to Oophorectomy in Women at Increased Risk of Ovarian Cancer: Protocol for a Nationwide Cross-Sectional Study With Prospective Follow-Up (HARMOny Study). JMIR Res Protoc. 2021 Jan 22;10(1):e24414. doi: 10.2196/24414.