Health After eaRly Menopause Due to Oophorectomy (HARMOny)

Favourable and Unfavourable Health Effects of Risk-Reducing Salpingo-Oophorectomy in Women With a High Genetic Risk of Ovarian Cancer

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.

Study Overview

• Status: Unknown
• Conditions: Cardiovascular Diseases; Quality of Life; Cognitive Decline; BRCA1 Mutation; BRCA2 Mutation; Bone Mineral Density; Surgical Menopause; Menopause Surgical
• Intervention / Treatment: Diagnostic test: CAC-score

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.

• Study Type: Observational
• Enrollment (Anticipated): 750

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1066CX
    • Netherlands Cancer Institute - Antoni van Leeuwenhoek

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: Female

• 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.

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Early-RRSO; RRSO before the age of 45 years; RRSO was done 10 or more years ago	Diagnostic test: CAC-score; Testing for possible unfavourable health effects of early surgical menopause; Other Names: Blood sampling; DXA-scan; Vertebral Fracture Assessment; Online cognition test (Amsterdam Cognition Scale); Quality of life questionnaire
Late-/non-RRSO group; Natural menopause ≥ 50 years of age; No RRSO ≤ age of 55; No treatment-induced menopause ≤ 50 years of age	Diagnostic test: CAC-score; Testing for possible unfavourable health effects of early surgical menopause; Other Names: Blood sampling; DXA-scan; Vertebral Fracture Assessment; Online cognition test (Amsterdam Cognition Scale); Quality of life questionnaire

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Due to the lack of estrogen we expect more atherosclerotic diseases.	4 years
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	Due to the lack of estrogen we expect more atherosclerotic diseases.	4 years
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	Due to the lack of estrogen we expect more atherosclerotic diseases.	4 years
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	Due to the lack of estrogen we expect more atherosclerotic diseases.	4 years
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	Loss of estrogen can result in more activity of osteoclasts and less activity of osteoblasts, The DXA-scan is corrected for age, with lower values representing a worse outcome	4 years
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	Loss of estrogen can result in more activity of osteoclasts and less activity of osteoblasts	4 years
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	Loss of estrogen can result in more activity of osteoclasts and less activity of osteoblasts	4 years
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	Loss of estrogen can result in more activity of osteoclasts and less activity of osteoblasts	4 years
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	There are some studies suggesting that an early menopause has an influence on cognition	4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	How do women with a premenopausal RRSO experience their life. The SF-36 questionnaire ranges from 36 to 149, with higher values representing a worse outcome	4 years
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.	How do women with a premenopausal RRSO experience their life. We measure the body image using the EORTC QLQ BR23, with ranges from 2 to 8, with higher values representing a worse outcome	4 years
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	How do women with a premenopausal RRSO experience their life. The FACT-ES questionnaire ranges from 0 to 76, with higher values representing a worse outcome	4 years
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	Have women with a premenopausal RRSO more urogenital complaints due to longer duration of estrogen deficiency. The SAQ questionnaire scale has questions with different weights as described in Thirlaway et al. 1996	4 years
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	Have women with a premenopausal RRSO more urogenital complaints due to longer duration of estrogen deficiency. The UDI-6 questionnaire scale has a range from 0 to 18, with higher values representing a worse outcome	4 years
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	Have women with a premenopausal RRSO more urogenital complaints due to longer duration of estrogen deficiency. The IIQ-7 questionnaire scale has a range from 0 to 24, with higher values representing a worse outcome	4 years
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.	Are some risk factors for cardiovascular disease more prevalent in women with a premenopausal RRSO	4 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	we will study the effect of RRSO on BC, contralateral breast cancer and ovarian cancer risk and prognosis after BC/ovarian cancer	4 years

Collaborators and Investigators

• Sponsor: The Netherlands Cancer Institute
• Collaborators: Radboud University Medical Center; Erasmus Medical Center; Dutch Cancer Society
• Investigators: Principal Investigator: Flora E van Leeuwen, Phd, NKI-AVL

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 11, 2019
• Primary Completion (Anticipated): September 30, 2021
• Study Completion (Anticipated): January 1, 2022

Study Registration Dates

• First Submitted: September 19, 2018
• First Submitted That Met QC Criteria: February 6, 2019
• First Posted (Actual): February 11, 2019

Study Record Updates

• Last Update Posted (Actual): September 14, 2020
• Last Update Submitted That Met QC Criteria: September 10, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: long-term; premature ovarian insufficiency
• Additional Relevant MeSH Terms: Mental Disorders; Neurocognitive Disorders; Cognition Disorders; Cardiovascular Diseases; Cognitive Dysfunction
• Other Study ID Numbers: M18HAR

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No